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Mitochondrial DNA (mtDNA) has been identified as a significant genetic biomarker in disease, cancer and evolution. Mitochondria function as modulators for regulating cellular metabolism. In the clinic, mtDNA variations (mutations/single nucleotide polymorphisms) and dysregulation of mitochondria-encoded genes are associated with survival outcomes among cancer patients. On the other hand, nuclear-encoded genes have been found to regulate mitochondria-encoded gene expression, in turn regulating mitochondrial homeostasis. These observations suggest that the crosstalk between the nuclear genome and mitochondrial genome is important for cellular function. Therefore, this review summarizes the significant mechanisms and functional roles of mtDNA variations (DNA level) and mtDNA-encoded genes (RNA and protein levels) in cancers and discusses new mechanisms of crosstalk between mtDNA and the nuclear genome.

Bulky DNA damage inducing chemotherapeutic cancer drugs such as cisplatin (CIS) and doxorubicin (DOX) are commonly used in the treatment of a variety of cancers. However, they often cause multi-organ toxicity, and the mechanisms underlying are not clear. Using cellular model, the present study showed that persistent endogenous reactive oxygen species (ROS) were stimulated after a single dose short treatment with CIS and DOX. ROS level correlated with the formation of DNA double-strand breaks (DSBs). Knockdown BRCA1, a key player involved in homologous recombination (HR), enhanced ROS accumulation. Whereas knockdown DNA-PKcs and overexpress BRCA1 to inhibit nonhomologous end-joining (NHEJ) repair pathway and restore HR can partially suppress ROS levels. These data indicated that ROS production is associated with DSB formation and repair which is likely a downstream event of DNA repair. Further studies showed that knockdown DNA repair regulators PP2A but not ATM, could partially reduce ROS too. The induction of ROS affected the level of proinflammatory cytokines interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). Collectively, the present study reveals that DNA repair associated metabolism change and oxidative stress may be a direct cause of the severe side effects associated with genotoxic chemotherapy cancer drugs., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Cancer is often called a disease of aging. There are numerous ways in which cancer epidemiology and behaviour change with the age of the patient. The molecular bases for these relationships remain largely underexplored. To characterise them, we analyse age-associations in the nuclear and mitochondrial somatic mutational landscape of 20,033 tumours across 35 tumour-types. Age influences both the number of mutations in a tumour (0.077 mutations per megabase per year) and their evolutionary timing. Specific mutational signatures are associated with age, reflecting differences in exogenous and endogenous oncogenic processes such as a greater influence of tobacco use in the tumours of younger patients, but higher activity of DNA damage repair signatures in those of older patients. We find that known cancer driver genes such as CDKN2A and CREBBP are mutated in age-associated frequencies, and these alter the transcriptome and predict for clinical outcomes. These effects are most striking in brain cancers where alterations like SUFU loss and ATRX mutation are age-dependent prognostic biomarkers. Using three cancer datasets, we show that age shapes the somatic mutational landscape of cancer, with clinical implications., (© 2022. The Author(s).)

Different types of DNA lesions forming in close vicinity, create clusters of damaged sites termed as "clustered/complex DNA damage" and they are considered to be a major challenge for DNA repair mechanisms resulting in significant repair delays and induction of genomic instability. Upon detection of DNA damage, the corresponding DNA damage response and repair (DDR/R) mechanisms are activated. The inability of cells to process clustered DNA lesions efficiently has a great impact on the normal function and survival of cells. If complex lesions are left unrepaired or misrepaired, they can lead to mutations and if persistent, they may lead to apoptotic cell death. In this in silico study, and through rigorous data mining, we have identified human genes that are activated upon complex DNA damage induction like in the case of ionizing radiation (IR) and beyond the standard DNA repair pathways, and are also involved in cancer pathways, by employing stringent bioinformatics and systems biology methodologies. Given that IR can cause repair resistant lesions within a short DNA segment (a few nm), thereby augmenting the hazardous and toxic effects of radiation, we also investigated the possible implication of the most biologically important of those genes in comorbid non-neoplastic diseases through network integration, as well as their potential for predicting survival in cancer patients.

Alternative lengthening of telomeres (ALT) is a telomere-elongation mechanism observed in ∼15% of cancer subtypes. Current models indicate that ALT is mediated by homology-directed repair mechanisms. By disrupting MSH6 gene expression, we show that the deficiency of MutSα (MSH2/MSH6) DNA mismatch repair complex causes striking telomere hyperextension. Mechanistically, we show MutSα is specifically recruited to telomeres in ALT cells by associating with the proliferating-cell nuclear antigen (PCNA) subunit of the ALT telomere replisome. We also provide evidence that MutSα counteracts Bloom (BLM) helicase, which adopts a crucial role in stabilizing hyper-extended telomeres and maintaining the survival of MutSα-deficient ALT cancer cells. Lastly, we propose a model in which MutSα deficiency impairs heteroduplex rejection, leading to premature initiation of telomere DNA synthesis that coincides with an accumulation of telomere variant repeats (TVRs). These findings provide evidence that the MutSα DNA mismatch repair complex acts to restrain unwarranted ALT., Competing Interests: Declaration of interests The authors have no conflicts of interest to declare., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The novel 1,2,3-triazolyl-appended N - and O -heterocycles containing amidine 4 - 11 and amidoxime 12 - 22 moiety were prepared and evaluated for their antiproliferative activities in vitro. Among the series of amidine-substituted heterocycles, aromatic diamidine 5 and coumarine amidine 11 had the most potent growth-inhibitory effect on cervical carcinoma (HeLa), hepatocellular carcinoma (HepG2) and colorectal adenocarcinoma (SW620), with IC 50 values in the nM range. Although compound 5 was toxic to non-tumor HFF cells, compound 11 showed certain selectivity. From the amidoxime series, quinoline amidoximes 18 and 20 showed antiproliferative effects on lung adenocarcinoma (A549), HeLa and SW620 cells emphasizing compound 20 that exhibited no cytostatic effect on normal HFF fibroblasts. Results of CD titrations and thermal melting experiments indicated that compounds 5 and 10 most likely bind inside the minor groove of AT-DNA and intercalate into AU-RNA. Compounds 6 , 9 and 11 bind to AT-DNA with mixed binding mode, most probably minor groove binding accompanied with aggregate binding along the DNA backbone.

Assembly and disassembly of DNA repair protein complexes at DNA damage sites are essential for maintaining genomic integrity. Investigating factors coordinating assembly of the base excision repair (BER) proteins DNA polymerase β (Polβ) and XRCC1 to DNA lesion sites identifies a role for Polβ in regulating XRCC1 disassembly from DNA repair complexes and, conversely, demonstrates Polβ's dependence on XRCC1 for complex assembly. LivePAR, a genetically encoded probe for live-cell imaging of poly(ADP-ribose) (PAR), reveals that Polβ and XRCC1 require PAR for repair-complex assembly, with PARP1 and PARP2 playing unique roles in complex dynamics. Further, BER complex assembly is modulated by attenuation/augmentation of NAD + biosynthesis. Finally, SIRT6 does not modulate PARP1 or PARP2 activation but does regulate XRCC1 recruitment, leading to diminished Polβ abundance at sites of DNA damage. These findings highlight coordinated yet independent roles for PARP1, PARP2, and SIRT6 and their regulation by NAD + bioavailability to facilitate BER., Competing Interests: Declaration of interests R.W.S. is a scientific consultant for Canal House Biosciences, but this company was not involved in this study, nor was the consulting work related to this study. The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aberrant activation of telomerase in human cancer is achieved by various alterations within the TERT promoter, including cancer-specific DNA hypermethylation of the TERT hypermethylated oncological region (THOR). However, the impact of allele-specific DNA methylation within the TERT promoter on gene transcription remains incompletely understood. Using allele-specific next-generation sequencing, we screened a large cohort of normal and tumor tissues (n = 652) from 10 cancer types and identified that differential allelic methylation (DAM) of THOR is restricted to cancerous tissue and commonly observed in major cancer types. THOR-DAM was more common in adult cancers, which develop through multiple stages over time, than in childhood brain tumors. Furthermore, THOR-DAM was especially enriched in tumors harboring the activating TERT promoter mutations (TPMs). Functional studies revealed that allele-specific gene expression of TERT requires hypomethylation of the core promoter, both in TPM and TERT WT cancers. However, the expressing allele with hypomethylated core TERT promoter universally exhibits hypermethylation of THOR, while the nonexpressing alleles are either hypermethylated or hypomethylated throughout the promoter. Together, our findings suggest a dual role for allele-specific DNA methylation within the TERT promoter in the regulation of TERT expression in cancer.

The gene TP53 , which encodes the tumor suppressor protein p53, is mutated in about 50% of cancers. In response to cell stressors like DNA damage and after treatment with DNA-damaging therapeutic agents, p53 acts as a transcription factor to activate subsets of target genes which carry out cell fates such as apoptosis, cell cycle arrest, and DNA repair. Target gene selection by p53 is controlled by a complex regulatory network whose response varies across contexts including treatment type, cell type, and tissue type. The molecular basis of target selection across these contexts is not well understood. Knowledge gained from examining p53 regulatory network profiles across different DNA-damaging agents in different cell types and tissue types may inform logical ways to optimally manipulate the network to encourage p53-mediated tumor suppression and anti-tumor immunity in cancer patients. This may be achieved with combination therapies or with p53-reactivating targeted therapies. Here, we review the basics of the p53 regulatory network in the context of differential responses to DNA-damaging agents; discuss recent efforts to characterize differential p53 responses across treatment types, cell types, and tissue types; and examine the relevance of evaluating these responses in the tumor microenvironment. Finally, we address open questions including the potential relevance of alternative p53 transcriptional functions, p53 transcription-independent functions, and p53-independent functions in the response to DNA-damaging therapeutics.

Evolutionary selection ensures specificity and efficiency in dynamic metastable macromolecular machines that repair DNA damage without releasing toxic and mutagenic intermediates. Here we examine non-homologous end joining (NHEJ) as the primary conserved DNA double-strand break (DSB) repair process in human cells. NHEJ has exemplary key roles in networks determining the development, outcome of cancer treatments by DSB-inducing agents, generation of antibody and T-cell receptor diversity, and innate immune response for RNA viruses. We determine mechanistic insights into NHEJ structural biochemistry focusing upon advanced small angle X-ray scattering (SAXS) results combined with X-ray crystallography (MX) and cryo-electron microscopy (cryo-EM). SAXS coupled to atomic structures enables integrated structural biology for objective quantitative assessment of conformational ensembles and assemblies in solution, intra-molecular distances, structural similarity, functional disorder, conformational switching, and flexibility. Importantly, NHEJ complexes in solution undergo larger allosteric transitions than seen in their cryo-EM or MX structures. In the long-range synaptic complex, X-ray repair cross-complementing 4 (XRCC4) plus XRCC4-like-factor (XLF) form a flexible bridge and linchpin for DNA ends bound to KU heterodimer (Ku70/80) and DNA-PKcs (DNA-dependent protein kinase catalytic subunit). Upon binding two DNA ends, auto-phosphorylation opens DNA-PKcs dimer licensing NHEJ via concerted conformational transformations of XLF-XRCC4, XLF-Ku80, and LigIV BRCT -Ku70 interfaces. Integrated structures reveal multifunctional roles for disordered linkers and modular dynamic interfaces promoting DSB end processing and alignment into the short-range complex for ligation by LigIV. Integrated findings define dynamic assemblies fundamental to designing separation-of-function mutants and allosteric inhibitors targeting conformational transitions in multifunctional complexes., (© 2021 The Authors. Protein Science published by Wiley Periodicals LLC on behalf of The Protein Society.)

An accumulation of evidence indicates the importance of DNA damage signaling in modulating immune responses. Indeed, understanding the mechanism that underlies signal transduction originating from DNA damage is vital to overcoming refractory cancer, particularly when cancer immune therapy is applied in combination with DNA damage-dependent radio/chemotherapy. In addition, immune-associated responses to such signals can aggravate the symptoms of infections, allergies, autoimmune disease, and aging. In this review, we discuss how cells transduce signals, triggered by DNA damage, from their origins to neighboring cells and how this affects immune and inflammatory responses., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Biological network-based strategies are useful in prioritizing genes associated with diseases. Several comprehensive human gene networks such as STRING, GIANT and HumanNet were developed and used in network-assisted algorithms to identify disease-associated genes. However, none of these networks are disease-specific and may not accurately reflect gene interactions for a specific disease. Aiming to improve disease gene prioritization using networks, we propose a Disease-Specific Network Enhancement Prioritization (DiSNEP) framework. DiSNEP first enhances a comprehensive gene network specifically for a disease through a diffusion process on a gene-gene similarity matrix derived from disease omics data. The enhanced disease-specific gene network thus better reflects true gene interactions for the disease and may improve prioritizing disease-associated genes subsequently. In simulations, DiSNEP that uses an enhanced disease-specific network prioritizes more true signal genes than comparison methods using a general gene network or without prioritization. Applications to prioritize cancer-associated gene expression and DNA methylation signal genes for five cancer types from The Cancer Genome Atlas (TCGA) project suggest that more prioritized candidate genes by DiSNEP are cancer-related according to the DisGeNET database than those prioritized by the comparison methods, consistently across all five cancer types considered, and for both gene expression and DNA methylation signal genes., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Genomic instability is the hallmark of various cancers with the increasing accumulation of DNA damage. The application of radiotherapy and chemotherapy in cancer treatment is typically based on this property of cancers. However, the adverse effects including normal tissues injury are also accompanied by the radiotherapy and chemotherapy. Targeted cancer therapy has the potential to suppress cancer cells' DNA damage response through tailoring therapy to cancer patients lacking specific DNA damage response functions. Obviously, understanding the broader role of DNA damage repair in cancers has became a basic and attractive strategy for targeted cancer therapy, in particular, raising novel hypothesis or theory in this field on the basis of previous scientists' findings would be important for future promising druggable emerging targets. In this review, we first illustrate the timeline steps for the understanding the roles of DNA damage repair in the promotion of cancer and cancer therapy developed, then we summarize the mechanisms regarding DNA damage repair associated with targeted cancer therapy, highlighting the specific proteins behind targeting DNA damage repair that initiate functioning abnormally duo to extrinsic harm by environmental DNA damage factors, also, the DNA damage baseline drift leads to the harmful intrinsic targeted cancer therapy. In addition, clinical therapeutic drugs for DNA damage and repair including therapeutic effects, as well as the strategy and scheme of relative clinical trials were intensive discussed. Based on this background, we suggest two hypotheses, namely "environmental gear selection" to describe DNA damage repair pathway evolution, and "DNA damage baseline drift", which may play a magnified role in mediating repair during cancer treatment. This two new hypothesis would shed new light on targeted cancer therapy, provide a much better or more comprehensive holistic view and also promote the development of new research direction and new overcoming strategies for patients.

Analysis and quantification of residual, unrepaired DNA double-strand breaks by detecting damage-associated γH2AX or 53BP1 foci is a promising approach to evaluate radiosensitivity or radiosensitization in tumor cells. Manual foci quantification by eye is well-established but unsatisfactory due to inconsistent foci numbers between different observers, lack of information about foci size and intensity and the time-consuming scoring process. Therefore, automated foci counting is an important goal. Several software solutions for automated foci counting in separately acquired fluorescence microscopy images have been established. The AKLIDES NUK technology by Medipan combines automated microscopy and image processing/ counting, enabling affordable high throughput foci analysis as a routine application. Using this machine, automated foci counting is well established for lymphocytes but has not yet been reported for adherent tumor cells with their irregularly shaped nuclei and heterogeneous foci textures. Here we aimed to use the AKLIDES NUK system for adherent tumor cells growing in clusters. We identified cell separation as a critical step to ensure fast and reliable automated nuclei detection. We validated our protocol for the fully automated quantification of (i) the IR-dose dependent increase and (ii) the ATM as well as PARP inhibitor-induced radiosensitization. Collectively, with this protocol the AKLIDES NUK system facilitates cost effective, fast and high throughput quantitative fluorescence microscopic analysis of DNA damage induced foci such as γH2AX and 53BP1 in adherent tumor cells., (Copyright © 2021. Published by Elsevier B.V.)

At the cellular level, DNA repair mechanisms are crucial in maintaining both genomic integrity and stability. DNA damage appears to be a central culprit in tumor onset and progression. Cyclin-dependent kinases (CDKs) and their regulatory partners coordinate the cell cycle progression. Aberrant CDK activity has been linked to a variety of cancers through deregulation of cell-cycle control. Besides DNA damaging agents and chromosome instability (CIN), disruptions in the levels of cell cycle regulators including cyclin-dependent kinase inhibitors (CDKIs) would result in unscheduled proliferation and cell division. The INK4 and Cip/Kip (CDK interacting protein/kinase inhibitor protein) family of CDKI proteins are involved in cell cycle regulation, transcription regulation, apoptosis, and cell migration. A thorough understanding of how these CDKIs regulate the DNA damage response through multiple signaling pathways may provide an opportunity to design efficient treatment strategies to inhibit carcinogenesis., (Copyright © 2021. Published by Elsevier B.V.)

The establishment and maintenance of genome packaging into chromatin contribute to define specific cellular identity and function. Dynamic regulation of chromatin organization and nucleosome positioning are critical to all DNA transactions-in particular, the regulation of gene expression-and involve the cooperative action of sequence-specific DNA-binding factors, histone modifying enzymes, and remodelers. Remodelers are molecular machines that generate various chromatin landscapes, adjust nucleosome positioning, and alter DNA accessibility by using ATP binding and hydrolysis to perform DNA translocation, which is highly regulated through sophisticated structural and functional conversations with nucleosomes. In this review, I first present the functional and structural diversity of remodelers, while emphasizing the basic mechanism of DNA translocation, the common regulatory aspects, and the hand-in-hand progressive increase in complexity of the regulatory conversations between remodelers and nucleosomes that accompanies the increase in challenges of remodeling processes. Next, I examine how, through nucleosome positioning, remodelers guide the regulation of gene expression. Finally, I explore various aspects of how alterations/mutations in remodelers introduce dissonance into the conversations between remodelers and nucleosomes, modify chromatin organization, and contribute to oncogenesis.

Aberrant DNA methylation is a fundamental characterization of epigenetics for carcinogenesis. Abnormality of DNA methylation-related functional elements (DMFEs) may lead to dysfunction of regulatory genes in the progression of cancers, contributing to prognosis of many cancers. There is an urgent need to construct a tool to comprehensively assess the impact of DMFEs on prognosis. Therefore, we developed SurvivalMeth (http://bio-bigdata.hrbmu.edu.cn/survivalmeth) to explore the prognosis-related DMFEs, which documented many kinds of DMFEs, including 309,465 CpG island-related elements, 104,748 transcript-related elements, 77,634 repeat elements, as well as cell-type specific 1,689,653 super enhancers (SE) and 1,304,902 CTCF binding regions for analysis. SurvivalMeth is a convenient tool which collected DNA methylation profiles of 36 cancers and allowed users to query their genes of interest in different datasets for prognosis. Furthermore, SurvivalMeth not only integrated different combinations, including single DMFE, multiple DMFEs, SEs and clinical data, to perform survival analysis on preupload data but also allowed for uploading customized DNA methylation profile of DMFEs from various diseases to analyze. SurvivalMeth provided a comprehensive resource and automated analysis for prognostic DMFEs, including DMFE methylation level, correlation analysis, clinical analysis, differential analysis, DMFE annotation, survival-related detailed result and visualization of survival analysis. In summary, we believe that SurvivalMeth will facilitate prognostic research of DMFEs in diverse cancers., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Up to now, many improvements have been made in providing more therapeutic strategies for cancer patients. The lack of susceptibility to common therapies like chemo- and radio-therapy is one of the reasons why we need more methods in the field of cancer therapy. DNA damage response (DDR) is a set of mechanisms which identifies DNA lesions and triggers the repair process for restoring DNA after causing an arrest in the cell cycle. The ability of DDR in maintaining the genome stability and integrity can be favorable to cancerous cells which are exposed to radiation therapy or are treated with chemotherapeutic agents. When DDR mechanisms are error-free in cancer cells, they can escape the expected cellular death and display resistance to treatment. In this regard, targeting different components of DDR can help to increase the susceptibility of advanced tumors to chemo- and radio-therapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data., Competing Interests: Declaration of interests G.M. and F.M. are cofounders and shareholders of Tailor Bio. R.B. owns equity in Ampressa Therapeutics. G.G. receives research funds from IBM and Pharmacyclics and is an inventor on patent applications related to MuTect, ABSOLUTE, MutSig, MSMuTect, and POLYSOLVER. I.L. is a consultant for PACT Pharma. B.J.R. is a consultant at and has ownership interest (including stock and patents) in Medley Genomics. N.M. has stock options in and has consulted for Achilles Therapeutics. C.S. acknowledges grant support from Pfizer, AstraZeneca, Bristol Myers Squibb, Roche-Ventana, Boehringer-Ingelheim, Archer Dx, and Ono Pharmaceutical; is an AstraZeneca Advisory Board Member and Chief Investigator for the MeRmaiD-1 clinical trial; has consulted for Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol Myers Squibb, Celgene, AstraZeneca, Illumina, Amgen, Genentech, Roche-Ventana, GRAIL, Medicxi, Bicycle Therapeutics, and the Sarah Cannon Research Institute; has stock options in Apogen Biotechnologies, Epic Bioscience, and GRAIL; and has stock options and is co-founder of Achilles Therapeutics., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Numerous epigenetic alterations are observed in cancer cells, and dysregulation of mono-ubiquitination of histone H2B (H2Bub1) has often been linked to tumorigenesis. H2Bub1 is a dynamic post-translational histone modification associated with transcriptional elongation and DNA damage response. Histone H2B monoubiquitination occurs in the site of lysine 120, written predominantly by E3 ubiquitin ligases RNF20/RNF40 and deubiquitinated by ubiquitin specific peptidase 22 (USP22). RNF20/40 is often altered in the primary tumors including colorectal cancer, breast cancer, ovarian cancer, prostate cancer, and lung cancer, and the loss of H2Bub1 is usually associated with poor prognosis in tumor patients. The purpose of this review is to summarize the current knowledge of H2Bub1 in transcription, DNA damage response and primary tumors. This review also provides novel options for exploiting the potential therapeutic target H2Bub1 in personalized cancer therapy., (Copyright © 2021 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Most of the genetic information has been lost or transferred to the nucleus during the evolution of mitochondria. Nevertheless, mitochondria have retained their own genome that is essential for oxidative phosphorylation (OXPHOS). In mammals, a gene-dense circular mitochondrial DNA (mtDNA) of about 16.5 kb encodes 13 proteins, which constitute only 1% of the mitochondrial proteome. Mammalian mtDNA is present in thousands of copies per cell and mutations often affect only a fraction of them. Most pathogenic human mtDNA mutations are recessive and only cause OXPHOS defects if present above a certain critical threshold. However, emerging evidence strongly suggests that the proportion of mutated mtDNA copies is not the only determinant of disease but that also the absolute copy number matters. In this review, we critically discuss current knowledge of the role of mtDNA copy number regulation in various types of human diseases, including mitochondrial disorders, neurodegenerative disorders and cancer, and during ageing. We also provide an overview of new exciting therapeutic strategies to directly manipulate mtDNA to restore OXPHOS in mitochondrial diseases., (© 2020 The Authors. FEBS Letters published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

A palindrome in DNA consists of two closely spaced or adjacent inverted repeats. Certain palindromes have important biological functions as parts of various cis-acting elements and protein binding sites. However, many palindromes are known as fragile sites in the genome, sites prone to chromosome breakage which can lead to various genetic rearrangements or even cell death. The ability of certain palindromes to initiate genetic recombination lies in their ability to form secondary structures in DNA which can cause replication stalling and double-strand breaks. Given their recombinogenic nature, it is not surprising that palindromes in the human genome are involved in genetic rearrangements in cancer cells as well as other known recurrent translocations and deletions associated with certain syndromes in humans. Here, we bring an overview of current understanding and knowledge on molecular mechanisms of palindrome recombinogenicity and discuss possible implications of DNA palindromes in carcinogenesis. Furthermore, we overview the data on known palindromic sequences in the human genome and efforts to estimate their number and distribution, as well as underlying mechanisms of genetic rearrangements specific palindromic sequences cause.

Focal chromosomal amplification contributes to the initiation of cancer by mediating overexpression of oncogenes 1-3 , and to the development of cancer therapy resistance by increasing the expression of genes whose action diminishes the efficacy of anti-cancer drugs. Here we used whole-genome sequencing of clonal cell isolates that developed chemotherapeutic resistance to show that chromothripsis is a major driver of circular extrachromosomal DNA (ecDNA) amplification (also known as double minutes) through mechanisms that depend on poly(ADP-ribose) polymerases (PARP) and the catalytic subunit of DNA-dependent protein kinase (DNA-PKcs). Longitudinal analyses revealed that a further increase in drug tolerance is achieved by structural evolution of ecDNAs through additional rounds of chromothripsis. In situ Hi-C sequencing showed that ecDNAs preferentially tether near chromosome ends, where they re-integrate when DNA damage is present. Intrachromosomal amplifications that formed initially under low-level drug selection underwent continuing breakage-fusion-bridge cycles, generating amplicons more than 100 megabases in length that became trapped within interphase bridges and then shattered, thereby producing micronuclei whose encapsulated ecDNAs are substrates for chromothripsis. We identified similar genome rearrangement profiles linked to localized gene amplification in human cancers with acquired drug resistance or oncogene amplifications. We propose that chromothripsis is a primary mechanism that accelerates genomic DNA rearrangement and amplification into ecDNA and enables rapid acquisition of tolerance to altered growth conditions.

Cancer is a global disease which has been disturbing researchers in medicine and seriously threatens patients' health and lifetime around the world in the past several decades. Due to the characteristics of cancer cells, such as uncontrollable cell proliferation, cell invasion and metastasis to surrounding tissues, lower grade of differentiation, higher telomerase activity and others, it has been one of the most usual lethal factors, next to heart disease in incidence. Cancer mortality can be decreased by early diagnosis, and the people who with treatment at an early stage have an obvious improved survival rate. Consequently, early detection is significant for better understanding the pathogenesis of cancer and improving the prognosis of patients. In situ detection technique is a vital tool for imaging and cellular pathology research, which can provide effective information about tumor markers in the early cancer detection. In view of low expression of most tumor markers in the early stage of cancers, detection techniques based on DNA signal amplification and DNA nanodevices can provide a strong support for the diagnosis and detection of cancers. In this review, we summarize the research progress of different analytical techniques for detecting various tumor markers that have been reported in recent years. We compare different DNA amplification and nanodevices, then provide guidance and suggestions for better understanding in situ analysis of cancer cells.

Transposable elements (TEs) drive genome evolution and are a notable source of pathogenesis, including cancer. While CpG methylation regulates TE activity, the locus-specific methylation landscape of mobile human TEs has to date proven largely inaccessible. Here, we apply new computational tools and long-read nanopore sequencing to directly infer CpG methylation of novel and extant TE insertions in hippocampus, heart, and liver, as well as paired tumor and non-tumor liver. As opposed to an indiscriminate stochastic process, we find pronounced demethylation of young long interspersed element 1 (LINE-1) retrotransposons in cancer, often distinct to the adjacent genome and other TEs. SINE-VNTR-Alu (SVA) retrotransposons, including their internal tandem repeat-associated CpG island, are near-universally methylated. We encounter allele-specific TE methylation and demethylation of aberrantly expressed young LINE-1s in normal tissues. Finally, we recover the complete sequences of tumor-specific LINE-1 insertions and their retrotransposition hallmarks, demonstrating how long-read sequencing can simultaneously survey the epigenome and detect somatic TE mobilization., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Whilst DNA cytosine methylation is the oldest and most well-studied epigenetic modification, basking in its glory days, it may be soon overshadowed by the new kid on the block: RNA adenosine methylation. This juxtaposition is indeed superficial, and a deep exploration toward the fundamental requirements for these essential epigenetic marks provides a clear perspective on their converging and synergistic roles. The recent discovery that both of these modifications are essential for preventing inappropriate activation of the intracellular innate immune responses to endogenous transcripts has provided a lot of interest in targeting them therapeutically as a means to improve cancer immunogenicity. Here we discuss the potential physiological function for DNA and RNA methylation in normal hematopoiesis and how these pervasive epigenetic marks are exploited in cancer, and provide suggestions for future research with a focus on leveraging this knowledge to uncover novel therapeutic targets., (Copyright © 2020 ISEH -- Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Platinum drugs are among the most effective anticancer agents, but their mode of action is still not fully understood. We therefore carried out a systematic investigation on the cellular activities of cisplatin, carboplatin and oxaliplatin in A498 kidney cancer cells. Cytotoxicity was higher for cisplatin and oxaliplatin compared to carboplatin, with induction of apoptosis as the preferred mode of cell death. Gene expression profiling displayed modulation of genes related to DNA damage response/repair, cell cycle regulation and apoptosis which was more pronounced upon oxaliplatin treatment. Furthermore, repression of specific DNA repair genes was restricted to oxaliplatin. Transcriptional level observations were further analyzed on the functional level. Uptake studies revealed low intracellular platinum accumulation and DNA platination upon carboplatin treatment. Removal of overall DNA platination was comparable for the three drugs. However, no processing of oxaliplatin-induced interstrand crosslinks was observed. Cisplatin and carboplatin influenced cell cycle distribution comparably, while oxaliplatin had no effect. Altogether, we found a similar mode of action for cisplatin and carboplatin, while the activity of oxaliplatin appeared to differ. This might be clinically relevant as due to the difference in mode of action oxaliplatin could be active in tumors which show resistance towards cisplatin and carboplatin.

Epigenetic modifications govern gene expression by guiding the human genome on 'what to express and what not to'. DNA methyltransferases (DNMTs) establish methylation patterns on DNA, particularly in CpG islands, and such patterns play a major role in gene silencing. DNMTs are a family of proteins/enzymes (DNMT1, 2, 3A, 3B, and 3L), among which, DNMT1 (maintenance methyltransferase) and DNMT3 (de novo methyltransferases) that direct mammalian development and genome imprinting are highly investigated. In recent decades, many studies revealed a strong association of DNA methylation patterns with gene expression in various clinical conditions. Differential expression of DNMT3 family proteins and their splice variants result in changes in methylation patterns and such alterations have been associated with the initiation and progression of various diseases, especially cancer. This review will discuss the aberrant modifications generated by DNMT3 proteins under various clinical conditions, suggesting a potential signature for de novo methyltransferases in targeted disease therapy. Further, this review discusses the possibility of using 'CpG island methylation signatures' as promising biomarkers and emphasizes 'targeted hypomethylation' by disrupting the interaction of specific DNMT-protein complexes as the future of cancer therapeutics., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2020 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Although the eukaryotic genome is mainly comprised of linear chromosomal DNA, genes can also be found outside of chromosomes. The unconventional presence of extrachromosomal genes is usually found to be circular, and these structures are named extrachromosomal circular DNA (eccDNA), which are often observed in cancer cells. Various types of eccDNA including small polydispersed DNA (spcDNA), telomeric cirlces, microDNA, etc. have been discovered. Among these eccDNA, extrachromosomal DNA (ecDNA), which encompasses the full spectrum of large, gene-containing extrachromosomal particles, has regained great research interest due to recent technological advances such as next-generation sequencing and super-resolution microscopy. In this review, we summarize the different types of eccDNA and discuss the role of eccDNA, especially ecDNA in tumor heterogeneity and progression. Additionally, we discuss some possible future investigative directions related to ecDNA biogenesis and its clinical application., Competing Interests: Declaration of Competing Interest Authors declare no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Propagation of clonal regulatory programs contributes to cancer development. It is poorly understood how epigenetic mechanisms interact with genetic drivers to shape this process. Here, we combine single-cell analysis of transcription and DNA methylation with a Luria-Delbrück experimental design to demonstrate the existence of clonally stable epigenetic memory in multiple types of cancer cells. Longitudinal transcriptional and genetic analysis of clonal colon cancer cell populations reveals a slowly drifting spectrum of epithelial-to-mesenchymal transcriptional identities that is seemingly independent of genetic variation. DNA methylation landscapes correlate with these identities but also reflect an independent clock-like methylation loss process. Methylation variation can be explained as an effect of global trans-acting factors in most cases. However, for a specific class of promoters-in particular, cancer-testis antigens-de-repression is correlated with and probably driven by loss of methylation in cis. This study indicates how genetic sub-clonal structure in cancer cells can be diversified by epigenetic memory.

Main factors involved in carcinogenesis are associated with somatic mutations in oncogenes and tumor suppressor genes representing changes in the DNA nucleotide sequence. Epigenetic changes, such as aberrant DNA methylation, modifications of histone proteins, and chromatin remodeling, are equally important in the development of human neoplasms. From this perspective, mutations in the genes encoding key participants of epigenetic regulation are of particular interest including enzymes that methylate/demethylate DNA, enzymes that covalently attach or remove regulatory signals from histones, components of nucleosome remodeling multiprotein complexes, auxiliary proteins and cofactors of the above-mentioned molecules. This review describes both germline and somatic mutations in the key epigenetic regulators with emphasis on the latter ones in the solid human tumors, as well as considers functional consequences of these mutations on the cellular level. In addition, clinical associations of the somatic mutations in epigenetic regulators are presented, as well as DNA diagnostics of hereditary cancer syndromes due to germline mutations in the SMARC proteins and chemotherapy drugs directly affecting the altered epigenetic mechanisms for treatment of patients with solid neoplasms. The review is intended for a wide range of molecular biologists, geneticists, oncologists, and associated specialists.

Cytosolic DNA sensing, the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, is an important novel role in the immune system. Multiple STING agonists were developed for cancer therapy study with great results achieved in pre-clinical work. Recent progress in the mechanical understanding of STING pathway in IFN production and T cell priming, indicates its promising role for cancer immunotherapy. STING agonists co-administrated with other cancer immunotherapies, including cancer vaccines, immune checkpoint inhibitors such as anti-programmed death 1 and cytotoxic T lymphocyte-associated antigen 4 antibodies, and adoptive T cell transfer therapies, would hold a promise of treating medium and advanced cancers. Despite the applications of STING agonists in cancer immunotherapy, lots of obstacles remain for further study. In this review, we mainly examine the biological characters, current applications, challenges, and future directions of cGAS-STING in cancer immunotherapy.

Tumor-derived exosomes are nano-sized vesicles acting as multi-signal devices influencing tumor growth at local and distant sites. Exosomes are derived from the endolysosomal compartment and can shuttle diverse biomolecules like nucleic acids (microRNAs and DNA fragments), lipids, proteins, and even pharmacological compounds from a donor cell to recipient cells. The transfer of cargo to recipient cells enables tumor-derived exosomes to influence diverse cellular functions like proliferation, cell survival, and migration in recipient cells, highlighting tumor-derived exosomes as important players in communication within the tumor microenvironment and at distant sites. In this review, we discuss the mechanisms associated with exosome biogenesis and cargo sorting. In addition, we highlight the communication of tumor-derived exosomes in the tumor microenvironment during different phases of tumor development, focusing on angiogenesis, immune escape mechanisms, drug resistance, and metastasis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In this work, the new polysaccharide-platinum conjugates of 5-aminosalicylic acid modified lycium barbarum polysaccharide linking platinum compounds were designed in order to construct an anticancer metal drug delivery system. The multiple analysis methods were used to describe the chemical structure and physical properties of the polysaccharide-metal conjugates. The results showed that 5-aminosalicylic acid successfully acted as linker which was covalently bound between polysaccharide and platinum compound. The morphology and rheological properties of polysaccharide have been changed by the formation of conjugates, which exhibited certain inhibition specificity to A549 (human lung cancer cell line). The agarose gel electrophoresis and fluorescence microscopy results demonstrated that such conjugates promoted the unwinding of DNA and could significantly damage the nucleus of A549 cells. Cell cycle analyzing the Pt complex of conjugates could cause intracellular DNA damage and induced G2 phase arrest. So, polysaccharide-platinum conjugates might find a range of applications, for example in metal anticancer drug delivery., Competing Interests: Declaration of competing interest The authors declare no competing financial interest., (Copyright © 2020. Published by Elsevier Inc.)

The term "epigenetic" is used to refer to heritable alterations in chromatin that are not due to changes in DNA sequence. Different growth factors and vascular genes mediate the angiogenic process, which is regulated by epigenetic states of genes. The aim of this article is to analyze the role of epigenetic mechanisms in the control and regulation of tumor angiogenetic processes. The reversibility of epigenetic events in contrast to genetic aberrations makes them potentially suitable for therapeutic intervention. In this context, DNA methyltransferase (DNMT) and HDAC inhibitors indirectly-via the tumor cells-exhibit angiostatic effects in vivo, and inhibition of miRNAs can contribute to the development of novel anti-angiogenesis therapies., (© 2019 John Wiley & Sons Ltd.)

Accumulating evidence has demonstrated that transcriptional regulation is affected by DNA methylation. Understanding the perturbation of DNA methylation-mediated regulation between transcriptional factors (TFs) and targets is crucial for human diseases. However, the global landscape of DNA methylation-mediated transcriptional dysregulation (DMTD) across cancers has not been portrayed. Here, we systematically identified DMTD by integrative analysis of transcriptome, methylome and regulatome across 22 human cancer types. Our results revealed that transcriptional regulation was affected by DNA methylation, involving hundreds of methylation-sensitive TFs (MethTFs). In addition, pan-cancer MethTFs, the regulatory activity of which is generally affected by DNA methylation across cancers, exhibit dominant functional characteristics and regulate several cancer hallmarks. Moreover, pan-cancer MethTFs were found to be affected by DNA methylation in a complex pattern. Finally, we investigated the cooperation among MethTFs and identified a network module that consisted of 43 MethTFs with prognostic potential. In summary, we systematically dissected the transcriptional dysregulation mediated by DNA methylation across cancer types, and our results provide a valuable resource for both epigenetic and transcriptional regulation communities., (© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Herein, we present a spectroscopic (CD and UV) and SEM study of a phenylalanine derivative carrying a terminal alkyne moiety and indicated by us CF3IIIPhe, with particular attention to its interaction with Cu(II) cation and some biological macromolecules, as well as a preliminary evaluation of its effect on cancerous cells. CD spectroscopy evidenced the ability of CF3IIIPhe to interact with tel 26 and c-myc, two quadruplex DNA (G4 DNA) models explored in this study. Other CD and UV studies revealed the ability of the unnatural amino acid to form aggregates in aqueous solution, to bind Cu(II) cation, and to interact with bovine serum albumin (BSA). Cellular studies demonstrated CF3IIIPhe antiproliferative activity on PC3 cells. Its ability to bind telomeric DNA was verified with tel 26 by CD investigation and SEM analysis, that revealed a noteworthy change in DNA morphology (mainly based on nanosphere structures) by CF3IIIPhe, confirming its G4-DNA binding ability already evidenced by spectroscopy., Competing Interests: Declaration of competing interest There are no conflicts to declare., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Rationale : Loss of DNA damage repair (DDR) in the tumor is an established hallmark of sensitivity to DNA damaging agents such as chemotherapy. However, there has been scant investigation into gain-of-function alterations of DDR genes in cancer. This study aims to investigate to what extent copy number amplification of DDR genes occurs in cancer, and what are their impacts on tumor genome instability, patient prognosis and therapy outcome. Methods : Retrospective analysis was performed on the clinical, genomics, and pharmacogenomics data from 10,489 tumors, matched peripheral blood samples, and 1,005 cancer cell lines. The key discoveries were verified by an independent patient cohort and experimental validations. Results : This study revealed that 13 of the 80 core DDR genes were significantly amplified and overexpressed across the pan-cancer scale. Tumors harboring DDR gene amplification exhibited decreased global mutation load and mechanism-specific mutation signature scores, suggesting an increased DDR proficiency in the DDR amplified tumors. Clinically, patients with DDR gene amplification showed poor prognosis in multiple cancer types. The most frequent Nibrin ( NBN ) gene amplification in ovarian cancer tumors was observed in 15 out of 31 independent ovarian cancer patients. NBN overexpression in breast and ovarian cancer cells leads to BRCA1-dependent olaparib resistance by promoting the phosphorylation of ATM-S1981 and homology-dependent recombination efficiency. Finally, integration of the cancer pharmacogenomics database of 37 genome-instability targeting drugs across 505 cancer cell lines revealed significant correlations between DDR gene copy number amplification and DDR drug resistance, suggesting candidate targets for increasing patient treatment response. Principal Conclusions : DDR gene amplification can lead to chemotherapy resistance and poor overall survival by augmenting DDR. These amplified DDR genes may serve as actionable clinical biomarkers for cancer management., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Alternative lengthening of telomeres (ALT) is a mechanism of telomere maintenance that is observed in many of the most recalcitrant cancer subtypes. Telomeres in ALT cancer cells exhibit a distinctive nucleoprotein architecture shaped by the mismanagement of chromatin that fosters cycles of DNA damage and replicative stress that activate homology-directed repair (HDR). Mutations in specific chromatin-remodeling factors appear to be key determinants of the emergence and survival of ALT cancer cells. However, these may represent vulnerabilities for the targeted elimination of ALT cancer cells that infiltrate tissues and organs to become devastating tumors. In this review we examine recent findings that provide new insights into the factors and mechanisms that mediate telomere length maintenance and survival of ALT cancer cells., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: In cancer, mutations of DNA methylation modification genes have crucial roles for epigenetic modifications genome-wide, which lead to the activation or suppression of important genes including tumor suppressor genes. Mutations on the epigenetic modifiers could affect the enzyme activity, which would result in the difference in genome-wide methylation profiles and, activation of downstream genes. Therefore, we investigated the effect of mutations on DNA methylation modification genes such as DNMT1, DNMT3A, MBD1, MBD4, TET1, TET2 and TET3 through a pan-cancer analysis., Methods: First, we investigated the effect of mutations in DNA methylation modification genes on genome-wide methylation profiles. We collected 3,644 samples that have both of mRNA and methylation data from 12 major cancer types in The Cancer Genome Atlas (TCGA). The samples were divided into two groups according to the mutational signature. Differentially methylated regions (DMR) that overlapped with the promoter region were selected using minfi and differentially expressed genes (DEG) were identified using EBSeq. By integrating the DMR and DEG results, we constructed a comprehensive DNA methylome profiles on a pan-cancer scale. Second, we investigated the effect of DNA methylations in the promoter regions on downstream genes by comparing the two groups of samples in 11 cancer types. To investigate the effects of promoter methylation on downstream gene activations, we performed clustering analysis of DEGs. Among the DEGs, we selected highly correlated gene set that had differentially methylated promoter regions using graph based sub-network clustering methods., Results: We chose an up-regulated DEGs cluster where had hypomethylated promoter in acute myeloid leukemia (LAML) and another down-regulated DEGs cluster where had hypermethylated promoter in colon adenocarcinoma (COAD). To rule out effects of gene regulation by transcription factor (TF), if differentially expressed TFs bound to the promoter of DEGs, that DEGs did not included to the gene set that effected by DNA methylation modifiers. Consequently, we identified 54 hypomethylated promoter DMR up-regulated DEGs in LAML and 45 hypermethylated promoter DMR down-regulated DEGs in COAD., Conclusions: Our study on DNA methylation modification genes in mutated vs. non-mutated groups could provide useful insight into the epigenetic regulation of DEGs in cancer.

Cells manage to survive, thrive, and divide with high accuracy despite the constant threat of DNA damage. Cells have evolved with several systems that efficiently repair spontaneous, isolated DNA lesions with a high degree of accuracy. Ionizing radiation and a few radiomimetic chemicals can produce clustered DNA damage comprising complex arrangements of single-strand damage and DNA double-strand breaks (DSBs). There is substantial evidence that clustered DNA damage is more mutagenic and cytotoxic than isolated damage. Radiation-induced clustered DNA damage has proven difficult to study because the spectrum of induced lesions is very complex, and lesions are randomly distributed throughout the genome. Nonetheless, it is fairly well-established that radiation-induced clustered DNA damage, including non-DSB and DSB clustered lesions, are poorly repaired or fail to repair, accounting for the greater mutagenic and cytotoxic effects of clustered lesions compared to isolated lesions. High linear energy transfer (LET) charged particle radiation is more cytotoxic per unit dose than low LET radiation because high LET radiation produces more clustered DNA damage. Studies with I-SceI nuclease demonstrate that nuclease-induced DSB clusters are also cytotoxic, indicating that this cytotoxicity is independent of radiogenic lesions, including single-strand lesions and chemically "dirty" DSB ends. The poor repair of clustered DSBs at least in part reflects inhibition of canonical NHEJ by short DNA fragments. This shifts repair toward HR and perhaps alternative NHEJ, and can result in chromothripsis-mediated genome instability or cell death. These principals are important for cancer treatment by low and high LET radiation., Competing Interests: The authors declare no conflict of interest.

Background: Dysregulation of alternative splicing (AS) is a critical signature of cancer. However, the regulatory mechanisms of cancer-specific AS events, especially the impact of DNA methylation, are poorly understood., Methods: By using The Cancer Genome Atlas (TCGA) SpliceSeq and TCGA data for ten solid tumor types, association analysis was performed to characterize the potential link between cancer-specific AS and DNA methylation. Functional and pathway enrichment analyses were performed, and the protein-protein interaction (PPI) network was constructed with the String website. The prognostic analysis was carried out with multivariate Cox regressions models., Results: 15,818 AS events in 3955 annotated genes were identified across ten solid tumor types. The different DNA methylation patterns between tumor and normal tissues at the corresponding alternative spliced exon boundaries were shown, and 51.3% of CpG sites (CpGs) revealed hypomethylated in tumors. Notably, 607 CpGs were found to be highly correlated with 369 cancer-specific AS events after permutation tests. Among them, the hypomethylated CpGs account for 52.7%, and the number of down-regulated exons was 173. Furthermore, we found 38 AS events in 35 genes could serve as new molecular biomarkers to predict patient survival., Conclusions: Our study described the relationship between DNA methylation and AS events across ten human solid tumor types and provided new insights into intragenic DNA methylation and exon usage during the AS process.

The recognition of DNA as an immune-stimulatory molecule is an evolutionarily conserved mechanism to initiate rapid innate immune responses against microbial pathogens. The cGAS-STING pathway was discovered as an important DNA-sensing machinery in innate immunity and viral defense. Recent advances have now expanded the roles of cGAS-STING to cancer. Highly aggressive, unstable tumors have evolved to co-opt this program to drive tumorigenic behaviors. In this review, we discuss the link between the cGAS-STING DNA-sensing pathway and antitumor immunity as well as cancer progression, genomic instability, the tumor microenvironment, and pharmacologic strategies for cancer therapy. SIGNIFICANCE: The cGAS-STING pathway is an evolutionarily conserved defense mechanism against viral infections. Given its role in activating immune surveillance, it has been assumed that this pathway primarily functions as a tumor suppressor. Yet, mounting evidence now suggests that depending on the context, cGAS-STING signaling can also have tumor and metastasis-promoting functions, and its chronic activation can paradoxically induce an immune-suppressive tumor microenvironment., (©2019 American Association for Cancer Research.)

Precise execution of the cell division cycle is vital for all organisms. The Cyclin dependent kinases (CDKs) are the main cell cycle drivers, however, their activities must be precisely fine-tuned to ensure orderly cell cycle progression. A major regulatory axis is guarded by WEE1 kinase, which directly phosphorylates and inhibits CDK1 and CDK2. The role of WEE1 in the G2/M cell-cycle phase has been thoroughly investigated, and it is a focal point of multiple clinical trials targeting a variety of cancers in combination with DNA-damaging chemotherapeutic agents. However, the emerging role of WEE1 in S phase has so far largely been neglected. Here, we review how WEE1 regulates cell-cycle progression highlighting the importance of this kinase for proper S phase. We discuss how its function is modulated throughout different cell-cycle stages and provide an overview of how WEE1 levels are regulated. Furthermore, we outline recent clinical trials targeting WEE1 and elaborate on the mechanisms behind the anticancer efficacy of WEE1 inhibition. Finally, we consider novel biomarkers that may benefit WEE1-inhibition approaches in the clinic., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The serine/threonine kinase AKT, also known as protein kinase B (PKB), is the major substrate to phosphoinositide 3-kinase (PI3K) and consists of three paralogs: AKT1 (PKBα), AKT2 (PKBβ) and AKT3 (PKBγ). The PI3K/AKT pathway is normally activated by binding of ligands to membrane-bound receptor tyrosine kinases (RTKs) as well as downstream to G-protein coupled receptors and integrin-linked kinase. Through multiple downstream substrates, activated AKT controls a wide variety of cellular functions including cell proliferation, survival, metabolism, and angiogenesis in both normal and malignant cells. In human cancers, the PI3K/AKT pathway is most frequently hyperactivated due to mutations and/or overexpression of upstream components. Aberrant expression of RTKs, gain of function mutations in PIK3CA, RAS, PDPK1, and AKT itself, as well as loss of function mutation in AKT phosphatases are genetic lesions that confer hyperactivation of AKT. Activated AKT stimulates DNA repair, e.g. double strand break repair after radiotherapy. Likewise, AKT attenuates chemotherapy-induced apoptosis. These observations suggest that a crucial link exists between AKT and DNA damage. Thus, AKT could be a major predictive marker of conventional cancer therapy, molecularly targeted therapy, and immunotherapy for solid tumors. In this review, we summarize the current understanding by which activated AKT mediates resistance to cancer treatment modalities, i.e. radiotherapy, chemotherapy, and RTK targeted therapy. Next, the effect of AKT on response of tumor cells to RTK targeted strategies will be discussed. Finally, we will provide a brief summary on the clinical trials of AKT inhibitors in combination with radiochemotherapy, RTK targeted therapy, and immunotherapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Topoisomerases are reported to resolve the topological problems of DNA during several cellular processes, such as DNA replication, transcription, recombination, and chromatin remodeling. Two types of topoisomerases (Topo I and II) accomplish their designated tasks by introducing single- or double-strand breaks within the duplex DNA molecules, and thus maintain the proper structural conditions of DNA to release the topological torsions, which is generated by unwinding of DNA to access coded information, in the course of replication, transcription, and other processes. Both the topoisomerases have been looked at as crucial targets against various types of cancers such as lung, melanoma, breast, and prostate cancers. Conceptually, targeting topoisomerases will disrupt both DNA replication and transcription, thereby leading to inhibition of cell division and consequently stopping the growth of actively dividing cancerous cells. Since the discovery of camptothecin (an alkaloid) as an inhibitor of Topo I in 1958, a number of derivatives of camptothecin were developed as potent inhibitors of Topo I. Two such derivatives of camptothecin, namely, topotecan and irinotecan, have been commonly used as US Food and Drug Administration (FDA) approved drugs against Topo I. Similarly, the first Topo II inhibitor, namely, etoposide, an analogue of podophyllotoxin, was developed in 1966 and got FDA approval as an anti-cancer drug in 1983. Subsequently, several other inhibitors of Topo II, such as doxorubicin, mitoxantrone, and teniposide, were developed. These drugs have been reported to cause accumulation of cytotoxic non-reversible DNA double-strand breaks (cleavable complex). Thus, the present review describes the anticancer potential of plant-derived secondary metabolites belonging to alkaloids, flavonoids and terpenoids directed against topoisomerases. Furthermore, in view of the recent advances made in the field of computer-aided drug design, the present review also discusses the use of computational approaches such as ADMET, molecular docking, molecular dynamics simulation and QSAR to assess and predict the safety, efficacy, potency and identification of these potent anti-cancerous therapeutic molecules., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Cancer cells undergo various rewiring of metabolism and dysfunction of epigenetic modification to support their biosynthetic needs. Although the major features of metabolic reprogramming have been elucidated, the global metabolic genes linking epigenetics were overlooked in pan-cancer., Objectives: Identifying the critical metabolic signatures with differential expressions which contributes to the epigenetic alternations across cancer types is an urgent issue for providing the potential targets for cancer therapy., Method: The differential gene expression and DNA methylation were analyzed by using the 5726 samples data from the Cancer Genome Atlas (TCGA)., Results: Firstly, we analyzed the differential expression of metabolic genes and found that cancer underwent overall metabolism reprogramming, which exhibited a similar expression trend with the data from the Gene Expression Omnibus (GEO) database. Secondly, the regulatory network of histone acetylation and DNA methylation according to altered expression of metabolism genes was summarized in our results. Then, the survival analysis showed that high expression of DNMT3B had a poorer overall survival in 5 cancer types. Integrative altered methylation and expression revealed specific genes influenced by DNMT3B through DNA methylation across cancers. These genes do not overlap across various cancer types and are involved in different function annotations depending on the tissues, which indicated DNMT3B might influence DNA methylation in tissue specificity., Conclusions: Our research clarifies some key metabolic genes, ACLY , SLC2A1 , KAT2A , and DNMT3B , which are most disordered and indirectly contribute to the dysfunction of histone acetylation and DNA methylation in cancer. We also found some potential genes in different cancer types influenced by DNMT3B . Our study highlights possible epigenetic disorders resulting from the deregulation of metabolic genes in pan-cancer and provides potential therapy in the clinical treatment of human cancer., Competing Interests: The authors declare that they have no conflicts of interest regarding the publication of this article., (Copyright © 2019 Yahui Shi et al.)

Chromatin is a macromolecular complex predominantly comprising DNA, histone proteins and RNA. The methylation of chromatin components is highly conserved as it helps coordinate the regulation of gene expression, DNA repair and DNA replication. Dynamic changes in chromatin methylation are essential for cell-fate determination and development. Consequently, inherited or acquired mutations in the major factors that regulate the methylation of DNA, RNA and/or histones are commonly observed in developmental disorders, ageing and cancer. This has provided the impetus for the clinical development of epigenetic therapies aimed at resetting the methylation imbalance observed in these disorders. In this Review, we discuss the cellular functions of chromatin methylation and focus on how this fundamental biological process is corrupted in cancer. We discuss methylation-based cancer therapies and provide a perspective on the emerging data from early-phase clinical trial therapies that target regulators of DNA and histone methylation. We also highlight promising therapeutic strategies, including monitoring chromatin methylation for diagnostic purposes and combination epigenetic therapy strategies that may improve immune surveillance in cancer and increase the efficacy of conventional and targeted anticancer drugs.