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Malignant tumors are among the most important causes of death worldwide. The pathogenesis of a malignant tumor is complex and has not been fully elucidated. Studies have shown that such pathogenesis is related to abnormal cell cycle progression. The expression levels of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors as well as functions of the cell cycle checkpoints determine whether the cell cycle progression is smooth. Cell-cycle-targeting drugs have the advantages of high specificity, low toxicity, low side effects, and low drug resistance. Identifying drugs that target the cell cycle and applying them in clinical treatments are expected to promote chemotherapeutic developments against malignant tumors. This article aims to review drugs targeted against the cell cycle and their action mechanisms. [ABSTRACT FROM AUTHOR]

Simple Summary: Around 50% of all human cancers are treated with radiotherapy. The effectiveness of radiotherapy is driven through causing DNA damage within the cancer cells; however, the cells respond by activating repair mechanisms that can lead to resistance to treatment. A promising strategy is to target one of these defence mechanisms, called the cell cycle checkpoint, using specific drugs/inhibitors that can be used in combination with radiotherapy. Here, we review evidence of investigations into inhibitors of two important proteins (Chk1 and Wee1) and how these can be used to increase the effectiveness of radiotherapy in cancer treatment. Radiotherapy is one of the main cancer treatments being used for ~50% of all cancer patients. Conventional radiotherapy typically utilises X-rays (photons); however, there is increasing use of particle beam therapy (PBT), such as protons and carbon ions. This is because PBT elicits significant benefits through more precise dose delivery to the cancer than X-rays, but also due to the increases in linear energy transfer (LET) that lead to more enhanced biological effectiveness. Despite the radiotherapy type, the introduction of DNA damage ultimately drives the therapeutic response through stimulating cancer cell death. To combat this, cells harbour cell cycle checkpoints that enables time for efficient DNA damage repair. Interestingly, cancer cells frequently have mutations in key genes such as TP53 and ATM that drive the G1/S checkpoint, whereas the G2/M checkpoint driven through ATR, Chk1 and Wee1 remains intact. Therefore, targeting the G2/M checkpoint through specific inhibitors is considered an important strategy for enhancing the efficacy of radiotherapy. In this review, we focus on inhibitors of Chk1 and Wee1 kinases and present the current biological evidence supporting their utility as radiosensitisers with different radiotherapy modalities, as well as clinical trials that have and are investigating their potential for cancer patient benefit. [ABSTRACT FROM AUTHOR]

Background RECIST criteria for progressive disease, partial response, and complete response, reflecting +20%, −30%, and −100% tumor size changes, respectively, are critical outcome variables in oncology clinical trials. Herein, we evaluated post-immunotherapy tumor size change correlation with outcomes. Methods We used a unique clinical trial data resource, a multicenter basket trial in patients with rare solid tumors treated with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) between 2017 and 2023 (National Cancer Institute/Southwest Oncology Group-sponsored DART trial [NCT02834013]) (open at 1083 sites at its peak). Outcome associations were evaluated by survival analysis techniques including Martingale residuals. Results In 638 evaluable patients, we found strong linear relationships between percent change in tumor measurement up to a 40%-50% increase and progression-free (PFS) and overall survival (OS) (both Cox regression P  < .001; landmark analyses based on day 65). Pearson R correlation between survival estimates and tumor change category were −0.94, −0.89, and −0.89 (PFS) and −0.84, −0.90, and −0.90 (OS) for median, 6-month (PFS), and 1-year (OS) and for 1-year (PFS) and 2-year (OS) estimates. Conclusions Percent change in tumor measurement per RECISTv1.1 (the sum of longest dimensions of target lesions) has a linear association with PFS and OS up to a 40% to 50% increase in tumor measurement in this cohort of patients with rare cancers who received combination immune checkpoint blockade. Quantitative first scan tumor measurement changes include important information to evaluate the potential efficacy of a therapy beyond the proportion of patients who achieve an objective response. [ABSTRACT FROM AUTHOR]

For an analog‐based design of novel Wee1 inhibitors, we profiled in vitro ADMET and in vivo PK properties of adavosertib. Based on the properties of adavosertib, we aimed to improve its metabolic stability by designing a novel target compound 1a with an aminosulfonyl group instead of the 2‐hydroxypropan‐2‐yl moiety in adavosertib. Derivatives of target compound 1a were synthesized and evaluated for Wee1 enzyme inhibition and liver microsomal phase I stability. We identified compound 1a as a sub‐nanomolar Wee1 inhibitor and 10 additional compounds with one‐digit nanomolar Wee1 inhibitory activity, among which seven compounds including 1a exhibited improved metabolic stabilities compared with adavosertib. However, MDA‐MB‐231 cell growth inhibitory activities of all synthesized compounds and Wee1 substrate phosphorylation inhibitory activities of selected compounds were inferior to adavosertib overall. Moreover, the representative compound 1a exhibited low permeability, which may be the reason for the low cellular activities of compound 1a. [ABSTRACT FROM AUTHOR]

BackgroundsColorectal adenocarcinoma (COAD), accounting for the most common subtype of colorectal cancer (CRC), is a kind of malignant digestive tumor. Some cell cycle checkpoints (CCCs) have been found to contribute to CRC progression, whereas the functional roles of a lot of CCCs, especially the integrated role of checkpoint mechanism in the cell cycle, remain unclear.Materials and methodsThe Genomic Data Commons (GDC) The Cancer Genome Atlas (TCGA) COAD cohort was retrieved as the training dataset, and GSE24551 and GSE29623 were downloaded from Gene Expression Omnibus (GEO) as the validation datasets. A total of 209 CCC-related genes were derived from the Gene Ontology Consortium and were subsequently enrolled in the univariate, multivariate, and least absolute shrinkage and selection operator (LASSO) Cox regression analyses, finally defining a CCC signature. Cell proliferation and Transwell assay analyses were utilized to evaluate the functional roles of signature-related CCCs. The underlying CCC signature, molecular characteristics, immune-related features, and therapeutic response were finally estimated. The Genomics of Drug Sensitivity in Cancer (GDSC) database was employed for the evaluation of chemotherapeutic responses.ResultsThe aberrant gene expression of CCCs greatly contributed to COAD development and progression. Univariate Cox regression analysis identified 27 CCC-related genes significantly affecting the overall survival (OS) of COAD patients; subsequently, LASSO analysis determined a novel CCC signature. Noticeably, CDK5RAP2, MAD1L1, NBN, RGCC, and ZNF207 were first identified to be correlated with the prognosis of COAD, and it was proven that all of them were significantly correlated with the proliferation and invasion of HCT116 and SW480 cells. In TCGA COAD cohort, CCC signature robustly stratified COAD patients into high and low CCC score groups (median OS: 57.24 months vs. unreached, p< 0.0001), simultaneously, with the good AUC values for OS prediction at 1, 2, and 3 years were 0.74, 0.78, and 0.77. Furthermore, the prognostic capacity of the CCC signature was verified in the GSE24551 and GSE29623 datasets, and the CCC signature was independent of clinical features. Moreover, a higher CCC score always indicated worse OS, regardless of clinical features, histological subtypes, or molecular subgroups. Intriguingly, functional enrichment analysis confirmed the CCC score was markedly associated with extracellular, matrix and immune (chemokine)-related signaling, cell cycle-related signaling, and metabolisms. Impressively, a higher CCC score was positively correlated with a majority of chemokines, receptors, immunostimulators, and anticancer immunity, indicating a relatively immune-promoting microenvironment. In addition, GSE173839, GSE25066, GSE41998, and GSE194040 dataset analyses of the underlying CCC signature suggested that durvalumab with olaparib and paclitaxel, taxane-anthracycline chemotherapy, neoadjuvant cyclophosphamide/doxorubicin with ixabepilone or paclitaxel, and immunotherapeutic strategies might be suitable for COAD patients with higher CCC score. Eventually, the GDSC database analysis showed that lower CCC scores were likely to be more sensitive to 5-fluorouracil, bosutinib, gemcitabine, gefitinib, methotrexate, mitomycin C, and temozolomide, while patients with higher CCC score seemed to have a higher level of sensitivity to bortezomib and elesclomol.ConclusionThe novel CCC signature exhibited a good ability for prognosis prediction for COAD patients, and the CCC score was found to be highly correlated with molecular features, immune-related characteristics, and therapeutic responses, which would greatly promote clinical management and precision medicine for COAD.

Abstract Continuous cell division is a hallmark of cancer, and the underlying mechanism is tumor genomics instability. Cell cycle checkpoints are critical for enabling an orderly cell cycle and maintaining genome stability during cell division. Based on their distinct functions in cell cycle control, cell cycle checkpoints are classified into two groups: DNA damage checkpoints and DNA replication stress checkpoints. The DNA damage checkpoints (ATM-CHK2-p53) primarily monitor genetic errors and arrest cell cycle progression to facilitate DNA repair. Unfortunately, genes involved in DNA damage checkpoints are frequently mutated in human malignancies. In contrast, genes associated with DNA replication stress checkpoints (ATR-CHK1-WEE1) are rarely mutated in tumors, and cancer cells are highly dependent on these genes to prevent replication catastrophe and secure genome integrity. At present, poly (ADP-ribose) polymerase inhibitors (PARPi) operate through “synthetic lethality” mechanism with mutant DNA repair pathways genes in cancer cells. However, an increasing number of patients are acquiring PARP inhibitor resistance after prolonged treatment. Recent work suggests that a combination therapy of targeting cell cycle checkpoints and PARPs act synergistically to increase the number of DNA errors, compromise the DNA repair machinery, and disrupt the cell cycle, thereby increasing the death rate of cancer cells with DNA repair deficiency or PARP inhibitor resistance. We highlight a combinational strategy involving PARP inhibitors and inhibition of two major cell cycle checkpoint pathways, ATM-CHK2-TP53 and ATR-CHK1-WEE1. The biological functions, resistance mechanisms against PARP inhibitors, advances in preclinical research, and clinical trials are also reviewed.

Background/purpose: WEE1 is a mitotic inhibitor at G2 checkpoint of the cell cycle that negatively regulates cyclin-dependent kinase 1 (CDK1) through inhibitory phosphorylation. This study assessed whether the expressions of both WEE1 and phosphorylated CDK1 in specimens of oral squamous cell carcinoma (OSCC) might predict the OSCC recurrence and progression. Materials and methods: This study used immunohistochemistry to examine the expressions of WEE1 and phosphorylated CDK1 proteins in 75 specimens of OSCC and 30 specimens of normal oral mucosa (NOM). Results: The mean WEE1 labeling index (LI) was significantly lower in 75 OSCC samples than in 30 NOM samples (P

After fertilization, remodeling of the oocyte and sperm genome is essential for the successful initiation of mitotic activity in the fertilized oocyte and subsequent proliferative activity of the early embryo. Despite the fact that the molecular mechanisms of cell cycle control in early mammalian embryos are in principle comparable to those in somatic cells, there are differences resulting from the specific nature of the gene totipotency of the blastomeres of early cleavage embryos. In this review, we focus on the Chk1 kinase as a key transduction factor in monitoring the integrity of DNA molecules during early embryogenesis. [ABSTRACT FROM AUTHOR]

Abstract Background As a DNA surveillance mechanism, cell cycle checkpoint has recently been discovered to be closely associated with lung adenocarcinoma (LUAD) prognosis. It is also an essential link in the process of DNA damage repair (DDR) that confers resistance to radiotherapy. Whether genes that have both functions play a more crucial role in LUAD prognosis remains unclear. Methods In this study, DDR-related genes with cell cycle checkpoint function (DCGs) were selected to investigate their effects on the prognosis of LUAD. The TCGA-LUAD cohort and two GEO external validation cohorts (GSE31210 and GSE42171) were performed to construct a prognosis model based on the least absolute shrinkage and selection operator (LASSO) regression. Patients were divided into high-risk and low-risk groups based on the model. Subsequently, the multivariate COX regression was used to construct a prognostic nomogram. The ssGSEA, CIBERSORT algorithm, TIMER tool, CMap database, and IC50 of chemotherapeutic agents were used to analyze immune activity and responsiveness to chemoradiotherapy. Results 4 DCGs were selected as prognostic signatures, and patients in the high-risk group had a lower overall survival (OS). The lower infiltration levels of immune cells and the higher expression levels of immune checkpoints appeared in the high-risk group. The damage repair pathways were upregulated, and chemotherapeutic agent sensitivity was poor in the high-risk group. Conclusions The 4-DCGs signature prognosis model we constructed could predict the survival rate, immune activity, and chemoradiotherapy responsiveness of LUAD patients.

The replication checkpoint is essential for accurate DNA replication and repair, and maintenance of genomic integrity when a cell is challenged with genotoxic stress. Several studies have defined the complement of proteins that change subcellular location in the budding yeast Saccharomyces cerevisiae following chemically induced DNA replication stress using methyl methanesulfonate (MMS) or hydroxyurea (HU). How these protein movements are regulated remains largely unexplored. We find that the essential checkpoint kinases Mec1 and Rad53 are responsible for regulating the subcellular localization of 159 proteins during MMS-induced replication stress. Unexpectedly, Rad53 regulation of the localization of 52 proteins is independent of its known kinase activator Mec1, and in some scenarios independent of Tel1 or the mediator proteins Rad9 and Mrc1. We demonstrate that Rad53 is phosphorylated and active following MMS exposure in cells lacking Mec1 and Tel1. This noncanonical mode of Rad53 activation depends partly on the retrograde signaling transcription factor Rtg3, which also facilitates proper DNA replication dynamics. We conclude that there are biologically important modes of Rad53 protein kinase activation that respond to replication stress and operate in parallel to Mec1 and Tel1.

Simple Summary: DNA damage response (DDR)-related proteins contribute to tumorigenesis, tumor progression, and drug resistance. Pharmacological inhibition of DDR-related proteins, such as checkpoint kinase 1 (Chk1), exerts antitumor effects but has serious side effects. Therefore, we attempted to specifically kill cancer cells with low concentrations of drugs by simultaneously inhibiting two DDR-related proteins. In this study, we demonstrated that the combined treatment with ataxia telangiectasia-mutated serine/threonine kinase (ATM) inhibitor (ATMi) and Chk1 inhibitor (Chk1i) exerts synergistic antitumor effects and induces cancer-specific synthetic lethality at low doses. The ATMi and Chk1i combination synergistically promotes CDK1 activation, resulting in the induction of apoptosis with enhanced cell cycle progression in cancer cells. Considering that the combined treatment exerts antitumor effects at one-tenth the concentrations described in previous reports, with high antitumor efficacy and few side effects it could be an effective treatment approach. Genetic abnormalities induce the DNA damage response (DDR), which enables DNA repair at cell cycle checkpoints. Although the DDR is thought to function in preventing the onset and progression of cancer, DDR-related proteins are also thought to contribute to tumorigenesis, tumor progression, and drug resistance by preventing irreparable genomic abnormalities from inducing cell death. In the present study, the combination of ataxia telangiectasia-mutated serine/threonine kinase (ATM) and checkpoint kinase 1 (Chk1) inhibition exhibited synergistic antitumor effects and induced synergistic lethality in colorectal cancer cells at a low dose. The ATM and Chk1 inhibitors synergistically promoted the activation of cyclin-dependent kinase 1 by decreasing the phosphorylation levels of T14 and Y15. Furthermore, the combined treatment increased the number of sub-G1-stage cells, phospho-histone H2A.X-positive cells, and TdT-mediated dUTP nick-end labeling-positive cells among colon cancer cells, suggesting that the therapy induces apoptosis. Finally, the combined treatment exhibited a robust antitumor activity in syngeneic tumor model mice. These findings should contribute to the development of new treatments for colorectal cancer that directly exploit the genomic instability of cancer cells. [ABSTRACT FROM AUTHOR]

Ataxia telangiectasia is a rare neurodegenerative disease caused by biallelic mutations in the ataxia telangiectasia mutated gene. No cure is currently available for these patients but positive effects on neurologic features in AT patients have been achieved by dexamethasone administration through autologous erythrocytes (EryDex) in phase II and phase III clinical trials, leading us to explore the molecular mechanisms behind the drug action. During these investigations, new ATM variants, which originated from alternative splicing of ATM messenger, were discovered, and detected in vivo in the blood of AT patients treated with EryDex. Some of the new ATM variants, alongside an in silico designed one, were characterized and examined in AT fibroblast cell lines. ATM variants were capable of rescuing ATM activity in AT cells, particularly in the nuclear role of DNA DSBs recognition and repair, and in the cytoplasmic role of modulating autophagy, antioxidant capacity and mitochondria functionality, all of the features that are compromised in AT but essential for neuron survival. These outcomes are triggered by the kinase and further functional domains of the tested ATM variants, that are useful for restoring cellular functionality. The in silico designed ATM variant eliciting most of the functionality recover may be exploited in gene therapy or gene delivery for the treatment of AT patients. [ABSTRACT FROM AUTHOR]

Continuous cell division is a hallmark of cancer, and the underlying mechanism is tumor genomics instability. Cell cycle checkpoints are critical for enabling an orderly cell cycle and maintaining genome stability during cell division. Based on their distinct functions in cell cycle control, cell cycle checkpoints are classified into two groups: DNA damage checkpoints and DNA replication stress checkpoints. The DNA damage checkpoints (ATM-CHK2-p53) primarily monitor genetic errors and arrest cell cycle progression to facilitate DNA repair. Unfortunately, genes involved in DNA damage checkpoints are frequently mutated in human malignancies. In contrast, genes associated with DNA replication stress checkpoints (ATR-CHK1-WEE1) are rarely mutated in tumors, and cancer cells are highly dependent on these genes to prevent replication catastrophe and secure genome integrity. At present, poly (ADP-ribose) polymerase inhibitors (PARPi) operate through "synthetic lethality" mechanism with mutant DNA repair pathways genes in cancer cells. However, an increasing number of patients are acquiring PARP inhibitor resistance after prolonged treatment. Recent work suggests that a combination therapy of targeting cell cycle checkpoints and PARPs act synergistically to increase the number of DNA errors, compromise the DNA repair machinery, and disrupt the cell cycle, thereby increasing the death rate of cancer cells with DNA repair deficiency or PARP inhibitor resistance. We highlight a combinational strategy involving PARP inhibitors and inhibition of two major cell cycle checkpoint pathways, ATM-CHK2-TP53 and ATR-CHK1-WEE1. The biological functions, resistance mechanisms against PARP inhibitors, advances in preclinical research, and clinical trials are also reviewed. [ABSTRACT FROM AUTHOR]

WEE1 is a mitotic inhibitor at G2 checkpoint of the cell cycle that negatively regulates cyclin-dependent kinase 1 (CDK1) through inhibitory phosphorylation. This study assessed whether the expressions of both WEE1 and phosphorylated CDK1 in specimens of oral squamous cell carcinoma (OSCC) might predict the OSCC recurrence and progression. This study used immunohistochemistry to examine the expressions of WEE1 and phosphorylated CDK1 proteins in 75 specimens of OSCC and 30 specimens of normal oral mucosa (NOM). The mean WEE1 labeling index (LI) was significantly lower in 75 OSCC samples than in 30 NOM samples (P < 0.001), whereas the mean phosphorylated CDK1 LI was significantly higher in 75 OSCC samples than in 30 NOM samples (P < 0.001). We found a significant association of low WEE1 LI (<21%) with OSCC recurrence (P = 0.047) and a significant association of low phosphorylated CDK1 LI (<10%) with larger tumor size (P = 0.011) and more advanced clinical stages (P = 0.021) of OSCC. Combined evaluation of WEE1 and phosphorylated CDK1 LI in specimens of OSCC may predict the OSCC recurrence and progression. [ABSTRACT FROM AUTHOR]

Malignant tumors are among the most important causes of death worldwide. The pathogenesis of a malignant tumor is complex and has not been fully elucidated. Studies have shown that such pathogenesis is related to abnormal cell cycle progression. The expression levels of cyclins, cyclin-dependent kinases (CDKs), and CDK inhibitors as well as functions of the cell cycle checkpoints determine whether the cell cycle progression is smooth. Cell-cycle-targeting drugs have the advantages of high specificity, low toxicity, low side effects, and low drug resistance. Identifying drugs that target the cell cycle and applying them in clinical treatments are expected to promote chemotherapeutic developments against malignant tumors. This article aims to review drugs targeted against the cell cycle and their action mechanisms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Song, Liu, Tang, Zhong, Zeng, Zhang, Zhou, Zhou, Cao, Zhang and Li.)

Background: As a DNA surveillance mechanism, cell cycle checkpoint has recently been discovered to be closely associated with lung adenocarcinoma (LUAD) prognosis. It is also an essential link in the process of DNA damage repair (DDR) that confers resistance to radiotherapy. Whether genes that have both functions play a more crucial role in LUAD prognosis remains unclear.Methods: In this study, DDR-related genes with cell cycle checkpoint function (DCGs) were selected to investigate their effects on the prognosis of LUAD. The TCGA-LUAD cohort and two GEO external validation cohorts (GSE31210 and GSE42171) were performed to construct a prognosis model based on the least absolute shrinkage and selection operator (LASSO) regression. Patients were divided into high-risk and low-risk groups based on the model. Subsequently, the multivariate COX regression was used to construct a prognostic nomogram. The ssGSEA, CIBERSORT algorithm, TIMER tool, CMap database, and IC50 of chemotherapeutic agents were used to analyze immune activity and responsiveness to chemoradiotherapy.Results: 4 DCGs were selected as prognostic signatures, and patients in the high-risk group had a lower overall survival (OS). The lower infiltration levels of immune cells and the higher expression levels of immune checkpoints appeared in the high-risk group. The damage repair pathways were upregulated, and chemotherapeutic agent sensitivity was poor in the high-risk group.Conclusions: The 4-DCGs signature prognosis model we constructed could predict the survival rate, immune activity, and chemoradiotherapy responsiveness of LUAD patients. [ABSTRACT FROM AUTHOR]

Abstract Although docetaxel (DTX) confers significant survival benefits in patients with castration‐resistant prostate cancer (CRPC), resistance to DTX inevitably occurs. Therefore, clarifying the mechanisms of DTX resistance may improve survival in patients with CRPC. Claspin plays a pivotal role in DNA replication stress and damage responses and is an essential regulator for the S‐phase checkpoint. CLSPN is an oncogenic gene that contributes to tumor proliferation in several human solid tumors. However, the clinical significance of claspin in prostate cancer (PCa) has not been examined. The present study aimed to elucidate the role of claspin and its relationship with DTX resistance in PCa. We immunohistochemically analyzed the expression of claspin in 89 PCa cases, of which 31 (35%) were positive for claspin. Claspin‐positive cases were associated with higher Gleason score, venous invasion, and perineural invasion. Kaplan–Meier analysis showed that high claspin expression was related to poor prostate‐specific antigen (PSA) relapse‐free prognosis. In a public database, high CLSPN expression was associated with poor PSA relapse‐free prognosis, Gleason score, T stage, lymph node metastasis, CRPC, and metastatic PCa. Claspin knockdown by siRNA decreased cell proliferation, upregulated DTX sensitivity, and suppressed the expression of Akt, Erk1/2, and CHK1 phosphorylation in DU145 and PC3 cell lines. Furthermore, claspin expression was much more upregulated in DTX‐resistant DU145 (DU145‐DR) than in parental DU145 cells. Claspin knockdown significantly upregulated the sensitivity to DTX in DU145‐DR cells. These results suggest that claspin plays an important role in PCa tumor progression and DTX resistance.

Despite a generally better prognosis than high-grade glioma (HGG), recurrence and malignant progression are the main causes for the poor prognosis and difficulties in the treatment of low-grade glioma (LGG). It is of great importance to learn about the risk factors and underlying mechanisms of LGG recurrence and progression. In this study, the transcriptome characteristics of four groups, namely, normal brain tissue and recurrent LGG (rLGG), normal brain tissue and secondary glioblastoma (sGBM), primary LGG (pLGG) and rLGG, and pLGG and sGBM, were compared using Chinese Glioma Genome Atlas (CGGA) and Genotype-Tissue Expression Project (GTEx) databases. In this study, 296 downregulated and 396 upregulated differentially expressed genes (DEGs) with high consensus were screened out. Univariate Cox regression analysis of data from The Cancer Genome Atlas (TCGA) yielded 86 prognostically relevant DEGs; a prognostic prediction model based on five key genes (HOXA1, KIF18A, FAM133A, HGF, and MN1) was established using the least absolute shrinkage and selection operator (LASSO) regression dimensionality reduction and multivariate Cox regression analysis. LGG was divided into high- and low-risk groups using this prediction model. Gene Set Enrichment Analysis (GSEA) revealed that signaling pathway differences in the high- and low-risk groups were mainly seen in tumor immune regulation and DNA damage-related cell cycle checkpoints. Furthermore, the infiltration of immune cells in the high- and low-risk groups was analyzed, which indicated a stronger infiltration of immune cells in the high-risk group than that in the low-risk group, suggesting that an immune microenvironment more conducive to tumor growth emerged due to the interaction between tumor and immune cells. The tumor mutational burden and tumor methylation burden in the high- and low-risk groups were also analyzed, which indicated higher gene mutation burden and lower DNA methylation level in the high-risk group, suggesting that with the accumulation of genomic mutations and epigenetic changes, tumor cells continued to evolve and led to the progression of LGG to HGG. Finally, the value of potential therapeutic targets for the five key genes was analyzed, and findings demonstrated that KIF18A was the gene most likely to be a potential therapeutic target. In conclusion, the prediction model based on these five key genes can better identify the high- and low-risk groups of LGG and lay a solid foundation for evaluating the risk of LGG recurrence and malignant progression. [ABSTRACT FROM AUTHOR]

Purpose Up to 20% of patients with biliary tract cancer (BTC) have alterations in DNA damage response (DDR) genes, including homologous recombination (HR) genes. Therefore, the DDR pathway could be a promising target for new drug development in BTC. We aim to investigate the anti-tumor effects using poly(ADP-ribose) polymerase (PARP) and WEE1 inhibitors in BTC. Materials and Methods We used 10 BTC cell lines to evaluate an anti-tumor effect of olaparib (a PARP inhibitor) and AZD1775 (a WEE1 inhibitor) in in vitro. Additionally, we established SNU869 xenograft model for in vivo experiments. Results In this study, we observed a modest anti-proliferative effect of olaparib. DNA double-strand break (DSB) and apoptosis were increased by olaparib in BTC cells. However, olaparib-induced DNA DSB was repaired through the HR pathway, and G2 arrest was induced to secure the time for repair. As AZD1775 typically regulates the G2/M checkpoint, we combined olaparib with AZD1775 to abrogate G2 arrest. We observed that AZD1775 downregulated p-CDK1, a G2/M cell cycle checkpoint protein, and induced early mitotic entry. AZD1775 also decreased CtIP and RAD51 expression and disrupted HR repair. In xenograft model, olaparib plus AZD1775 treatment reduced tumor growth more potently than did monotherapy with either drug. Conclusion This is the first study to suggest that olaparib combined with AZD1775 can induce synergistic anti-tumor effects against BTC. Combination therapy that blocks dual PARP and WEE1 has the potential to be further clinically developed for BTC patients. [ABSTRACT FROM AUTHOR]

Despite a generally better prognosis than high-grade glioma (HGG), recurrence and malignant progression are the main causes for the poor prognosis and difficulties in the treatment of low-grade glioma (LGG). It is of great importance to learn about the risk factors and underlying mechanisms of LGG recurrence and progression. In this study, the transcriptome characteristics of four groups, namely, normal brain tissue and recurrent LGG (rLGG), normal brain tissue and secondary glioblastoma (sGBM), primary LGG (pLGG) and rLGG, and pLGG and sGBM, were compared using Chinese Glioma Genome Atlas (CGGA) and Genotype-Tissue Expression Project (GTEx) databases. In this study, 296 downregulated and 396 upregulated differentially expressed genes (DEGs) with high consensus were screened out. Univariate Cox regression analysis of data from The Cancer Genome Atlas (TCGA) yielded 86 prognostically relevant DEGs; a prognostic prediction model based on five key genes (HOXA1, KIF18A, FAM133A, HGF, and MN1) was established using the least absolute shrinkage and selection operator (LASSO) regression dimensionality reduction and multivariate Cox regression analysis. LGG was divided into high- and low-risk groups using this prediction model. Gene Set Enrichment Analysis (GSEA) revealed that signaling pathway differences in the high- and low-risk groups were mainly seen in tumor immune regulation and DNA damage-related cell cycle checkpoints. Furthermore, the infiltration of immune cells in the high- and low-risk groups was analyzed, which indicated a stronger infiltration of immune cells in the high-risk group than that in the low-risk group, suggesting that an immune microenvironment more conducive to tumor growth emerged due to the interaction between tumor and immune cells. The tumor mutational burden and tumor methylation burden in the high- and low-risk groups were also analyzed, which indicated higher gene mutation burden and lower DNA methylation level in the high-risk group, suggesting that with the accumulation of genomic mutations and epigenetic changes, tumor cells continued to evolve and led to the progression of LGG to HGG. Finally, the value of potential therapeutic targets for the five key genes was analyzed, and findings demonstrated that KIF18A was the gene most likely to be a potential therapeutic target. In conclusion, the prediction model based on these five key genes can better identify the high- and low-risk groups of LGG and lay a solid foundation for evaluating the risk of LGG recurrence and malignant progression.

Radiation therapy (RT) is a standard treatment for solid tumors and about 50% of patients with cancer, including pediatric cancer, receive RT. While RT has significantly improved the overall survival and quality of life of cancer patients, its efficacy has still been markedly limited by radioresistance in a significant number of cancer patients (intrinsic or acquired), resulting in failure of the RT control of the disease. Radiation eradicates cancer cells mainly by causing DNA damage. However, radiation also concomitantly activates multiple prosurvival signaling pathways, which include those mediated by ATM, ATR, AKT, ERK, and NF-κB that promote DNA damage checkpoint activation/DNA repair, autophagy induction, and/or inhibition of apoptosis. Furthermore, emerging data support the role of YAP signaling in promoting the intrinsic radioresistance of cancer cells, which occurs through its activation of the transcription of many essential genes that support cell survival, DNA repair, proliferation, and the stemness of cancer stem cells. Together, these signaling pathways protect cancer cells by reducing the magnitude of radiation-induced cytotoxicity and promoting radioresistance. Thus, targeting these prosurvival signaling pathways could potentially improve the radiosensitivity of cancer cells. In this review, we summarize the contribution of these pathways to the radioresistance of cancer cells. [ABSTRACT FROM AUTHOR]

Abstract Background DNA damage is generated by various intrinsic and extrinsic sources such as reactive oxygen species (ROS) and environmental mutagens, and causes genomic alterations. DNA damage response (DDR) is activated to induce cell cycle arrest and DNA repair. Oxidation resistance 1 (OXR1) is a protein that defends cells against oxidative stress. We previously reported that OXR1 protein functions in the regulation of G2-phase cell cycle arrest in cells irradiated with gamma-rays, suggesting that OXR1 directly responds to DNA damage. Purpose To clarify the functions of OXR1 against ROS-independent DNA damage, HeLa and OXR1-depleted HeLa cells were treated with heavy-ion beams and the ROS-independent DNA-damaging agent methyl methanesulfonate (MMS). Results First, OXR1-depleted cells exhibited higher sensitivity to MMS and heavy-ion beams than control cells. Next, OXR1 depletion increased micronucleus formation and shortened the duration of G2-phase arrest after treatment with MMS or heavy-ion beams. These results suggest that OXR1 functions in the maintenance of cell survival and genome stability in response to DNA damage. Furthermore, the OXR1 protein level was increased by MMS and heavy-ion beams in HeLa cells. Conclusions Together with our previous study, the present study suggests that OXR1 plays an important role in the response to DNA damage, not only when DNA damage is generated by ROS.

Abstract Radiation therapy is a standard treatment for local disease control of solid tumors. Although radiation therapy has significantly improved the overall survival and quality of life of cancer patients, its efficacy has been limited by the development of radiation resistance and the presence of residual disease after therapy, leading to cancer recurrence. Radiation induces cytotoxicity in cancer cells, mainly by causing DNA damage. However, concurrently radiation can also activate multiple protective signaling pathways, such as ataxia telangiectasia mutated/ataxia telangiectasia mutated and Rad3‐related protein, phosphoinositide‐3‐kinase/protein kinase B, extracellular signal‐regulated kinase, and nuclear factor‐κB, which promote cell cycle checkpoint activation, leading to cell cycle arrest/DNA repair and inhibition of apoptosis. Conjointly, these signaling pathways protect cancer cells by reducing the magnitude of radiation‐induced cytotoxicity and promoting radioresistance of cancer cells. Thus, targeting these prosurvival pathways could have great potential for sensitizing cancer cells to radiation therapy. In the present review, we summarize the current literature on the radiation‐activated prosurvival signaling pathways that promote radioresistance.

Disruption of cell cycle checkpoints has been well established as a hallmark of cancer. In particular, the G1-S transition mediated by the cyclin D-cyclin-dependent kinase 4/6 (CDK4/6) pathway is dysregulated in more than 90% of melanoma cases. Therefore, tumor cells mainly rely on the G2-M checkpoint to halt the cell cycle in order to repair DNA damage. Here, we review the promising method of cell cycle-mediated synthetic lethality for melanoma treatment, which entails exploiting somatically acquired mutations in the G1-S transition with inhibitors of the G2-M transition in order to specifically kill melanoma cells. The idea stems from the theory that melanoma cells lacking G1-S checkpoints are particularly vulnerable to mitotic catastrophe when presented with G2-M checkpoint inhibition in addition to DNA damage, whereas normal cells with intact G1-S checkpoints should theoretically be spared. This review explores the link between cell cycle dysregulation and synthetic lethality in melanoma cells and discusses potential future applications for this treatment. [ABSTRACT FROM AUTHOR]

Summary: DNA damage often induces heterogeneous cell-fate responses, such as cell-cycle arrest and apoptosis. Through single-cell RNA sequencing (scRNA-seq), we characterize the transcriptome response of cultured colon cancer cell lines to 5-fluorouracil (5FU)-induced DNA damage. After 5FU treatment, a single population of colon cancer cells adopts three distinct transcriptome phenotypes, which correspond to diversified cell-fate responses: apoptosis, cell-cycle checkpoint, and stress resistance. Although some genes are regulated uniformly across all groups of cells, many genes showed group-specific expression patterns mediating DNA damage responses specific to the corresponding cell fate. Some of these observations are reproduced at the protein level by flow cytometry and are replicated in cells treated with other 5FU-unrelated genotoxic drugs, camptothecin and etoposide. This work provides a resource for understanding heterogeneous DNA damage responses involving fractional killing and chemoresistance, which are among the major challenges in current cancer chemotherapy.

Radiation therapy (RT) is a standard treatment for solid tumors and about 50% of patients with cancer, including pediatric cancer, receive RT. While RT has significantly improved the overall survival and quality of life of cancer patients, its efficacy has still been markedly limited by radioresistance in a significant number of cancer patients (intrinsic or acquired), resulting in failure of the RT control of the disease. Radiation eradicates cancer cells mainly by causing DNA damage. However, radiation also concomitantly activates multiple prosurvival signaling pathways, which include those mediated by ATM, ATR, AKT, ERK, and NF-κB that promote DNA damage checkpoint activation/DNA repair, autophagy induction, and/or inhibition of apoptosis. Furthermore, emerging data support the role of YAP signaling in promoting the intrinsic radioresistance of cancer cells, which occurs through its activation of the transcription of many essential genes that support cell survival, DNA repair, proliferation, and the stemness of cancer stem cells. Together, these signaling pathways protect cancer cells by reducing the magnitude of radiation-induced cytotoxicity and promoting radioresistance. Thus, targeting these prosurvival signaling pathways could potentially improve the radiosensitivity of cancer cells. In this review, we summarize the contribution of these pathways to the radioresistance of cancer cells.

Nijmegen breakage syndrome caused by biallelic pathogenic variants of the DNA‐damage response gene NBN, is characterized by severe microcephaly, cancer proneness, infertility, and karyotype abnormalities. We previously reported NBN variants in siblings suffering from fertility defects. Here, we identify a new founder NBN variant (c.442A>G, p.(Thr148Ala)) in Lebanese patients associated with isolated infertility. Functional analyses explored preserved or altered functions correlated with their remarkably mild phenotype. Transcript and protein analyses supported the use of an alternative transcript with in‐frame skipping of exons 4–5, leading to p84‐NBN protein with a preserved forkhead‐associated (FHA) domain. The level of NBN was dramatically reduced and the MRN complex delocalized to the cytoplasm. Interestingly, ataxia–elangiectasia mutated (ATM) also shifted from the nucleus to the cytoplasm, suggesting some interaction between ATM and the MRN complex at a steady state. The ATM pathway activation, attenuated in typical patients with NBS, appeared normal under camptothecin treatment in these new NBN‐related infertile patients. Cell cycle checkpoint defect was present in these atypical patients, although to a lesser extent than in typical patients with NBS. In conclusion, we report three new NBN‐related infertile patients and we suggest that preserved FHA domain could be responsible for the mild phenotype and intermediate DNA‐damage response defects. [ABSTRACT FROM AUTHOR]

Pancreatic adenocarcinoma upregulated factor (PAUF), also known as ZG16B, was previously found in the secretome of metastatic colorectal cancer cells. Here, we demonstrated the presence of PAUF at the intracellular level and its multiple effects on cancer progression. An initial decline of PAUF expression was observed at early stages of colorectal cancer followed by an increase at the metastatic site. PAUF was located at different cellular compartments: membrane-associated vesicles, endosomes, microtubule-associated vesicles, cell growth cones and the cell nucleus. PAUF loss in two colorectal cancer cell lines caused severe alterations in the cell phenotype and cell cycle, including tetraploidy, extensive genomic alterations, micronuclei and increased apoptosis. An exhaustive analysis of the PAUF interactome using different proteomic approaches revealed the presence of multiple components of the cell cycle, mitotic checkpoint, Wnt pathway and intracellular transport. Among the interacting proteins we found ZW10, a moonlighting protein with a dual function in membrane trafficking and mitosis. In addition, PAUF silencing was associated to APC loss and increased β-catenin nuclear expression. Altogether, our results suggest that PAUF depletion increases aneuploidy, promotes apoptosis and activates the Wnt/β-catenin pathway in colorectal cancer cells facilitating cancer progression. In summary, PAUF behaves as a multifunctional protein, with different roles in cancer progression according to the extra- or intracellular expression, suggesting a therapeutic value for colorectal cancer. [ABSTRACT FROM AUTHOR]

The combination of low dose of radiation and an anticancer drug is a potent strategy for cancer therapy. Nucleoside analogs are known to have a radiosensitizing effects via the inhibition of DNA damage repair after irradiation. Certain types of nucleoside analogs have the inhibitory effects on RNA synthesis, but not DNA synthesis, with multiple functions in cell cycle modulation and apoptosis. In this review, the most up-to-date findings regarding radiosensitizing nucleoside analogs will be discussed, focusing especially on the mechanisms of action. [ABSTRACT FROM AUTHOR]

Abstract The DNA Damage Response (DDR) is a complex network of biological processes that protect cells from accumulating aberrant DNA structures, thereby maintaining genomic stability and, as a consequence, preventing the development of cancer and other diseases. The DDR pathway is coordinated by a signaling cascade mediated by the PI3K-like kinases (PIKK) ATM and ATR and by their downstream kinases CHK2 and CHK1, respectively. Together, these kinases regulate several aspects of the cellular program in response to genomic stress. Much of our understanding of these kinases came from studies performed in the 1990s using yeast as a model organism. The purpose of this review is to present a historical perspective on the discovery of the DDR kinases in yeast and the importance of this model for the identification and functional understanding of their mammalian orthologues.

Maintenance of genome integrity is a key issue for all living organisms. Cells are constantly exposed to DNA damage due to replication or transcription, cellular metabolic activities leading to the production of Reactive Oxygen Species (ROS) or even exposure to DNA damaging agents such as UV light. However, genomes remain extremely stable, thanks to the permanent repair of DNA lesions. One key mechanism contributing to genome stability is the DNA Damage Response (DDR) that activates DNA repair pathways, and in the case of proliferating cells, stops cell division until DNA repair is complete. The signaling mechanisms of the DDR are quite well conserved between organisms including in plants where they have been investigated into detail over the past 20 years. In this review we summarize the acquired knowledge and recent advances regarding the DDR control of cell cycle progression. Studying the plant DDR is particularly interesting because of their mode of development and lifestyle. Indeed, plants develop largely post-embryonically, and form new organs through the activity of meristems in which cells retain the ability to proliferate. In addition, they are sessile organisms that are permanently exposed to adverse conditions that could potentially induce DNA damage in all cell types including meristems. In the second part of the review we discuss the recent findings connecting the plant DDR to responses to biotic and abiotic stresses.

DNA double-strand breaks (DSBs) pose a constant threat to genomic integrity. Such DSBs need to be repaired to preserve homeostasis at both the cellular and organismal levels. Hence, the DNA damage response (DDR) has evolved to repair these lesions and limit their toxicity. The initiation of DNA repair depends on the activation of the DDR, and we know that the strength of DDR signaling may differentially affect cellular viability. However, we do not fully understand what determines the cytotoxicity of a DSB. Recent work has identified genomic location, (in)correct DNA repair pathway usage, and cell-cycle position as contributors to DSB-induced cytotoxicity. In this review, we discuss how these determinants affect cytotoxicity, highlight recent discoveries, and identify open questions that could help to improve our understanding about cell fate decisions after a DNA DSB. Krenning et al. give an overview of determinants that affect the cellular toxicity of DNA double-strand breaks and discuss how these determinants affect cytotoxicity. The authors highlight recent discoveries and identify open questions that could help to improve our understanding about cell fate decisions after a DNA double-strand break. [ABSTRACT FROM AUTHOR]

The Tousled-like kinases (TLKs) are an evolutionarily conserved family of serine–threonine kinases that have been implicated in DNA replication, DNA repair, transcription, chromatin structure, viral latency, cell cycle checkpoint control and chromosomal stability in various organisms. The functions of the TLKs appear to depend largely on their ability to regulate the H3/H4 histone chaperone ASF1, although numerous TLK substrates have been proposed. Over the last few years, a clearer picture of TLK function has emerged through the identification of new partners, the definition of specific roles in development and the elucidation of their structural and biochemical properties. In addition, the TLKs have been clearly linked to human disease; both TLK1 and TLK2 are frequently amplified in human cancers and TLK2 mutations have been identified in patients with neurodevelopmental disorders characterized by intellectual disability (ID), autism spectrum disorder (ASD) and microcephaly. A better understanding of the substrates, regulation and diverse roles of the TLKs is needed to understand their functions in neurodevelopment and determine if they are viable targets for cancer therapy. In this review, we will summarize current knowledge of TLK biology and its potential implications in development and disease. [ABSTRACT FROM AUTHOR]

The ATR–dependent DNA damage checkpoint is one of the major checkpoint pathways. The interaction between the Rad17–RFC2-5 and 9–1–1 complexes is central to the ATR–Chk1 pathway. However, little is known about the regulation of the interaction. We recently showed that vertebrate Rad17 proteins share a conserved C-terminal tail and that the C-terminal tails have a conserved amino acid motif named iVERGE that must be intact for the interaction between Rad17 and the 9‒1‒1 complex. In human Rad17, the Y665 and S667 residues are conserved in iVERGE. The Rad17-S667 residue is phosphorylated by CK2, and the phosphorylation is important for the interaction with the 9‒1‒1 complex. Here, we show that a C-terminal threonine residue of Rad17, T670 in human Rad17, is constitutively phosphorylated in vivo. The T670 phosphorylation is important for the S667 phosphorylation, and vice versa. Phosphomimetic mutations in the T670 residue promote the interaction with the 9–1–1 complex. The T670 and Y665 residues show functional redundancy, and their roles are dependent on the S667 phosphorylation. Rad17-T670 is phosphorylated by casein kinase 1δ/ε. Our data suggest that iVERGE integrates multiple signaling pathways to regulate the ATR–Chk1 pathway. • Human Rad17 is constitutively phosphorylated in vivo on a C-terminal threonine, T670. • The T670 phosphorylation is important for the S667 phosphorylation, and vice versa. • Phosphomimetic mutations of the T670 promote interaction with the 9–1–1 complex. • The roles of T670 and Y665 residues are dependent on the S667 phosphorylation. • Rad17-T670 is phosphorylated by casein kinase 1δ/ ε. [ABSTRACT FROM AUTHOR]

Schlafen 11 (SLFN11) sensitizes cells to a broad range of anti-cancer drugs including platinum derivatives (cisplatin and carboplatin), inhibitors of topoisomerases (irinotecan, topotecan, doxorubicin, daunorubicin, mitoxantrone and etoposide), DNA synthesis inhibitors (gemcitabine, cytarabine, hydroxyurea and nucleoside analogues), and poly(ADPribose) polymerase (PARP) inhibitors (olaparib, rucaparib, niraparib and talazoparib). In spite of their different primary mechanisms of action, all these drugs damage DNA during S-phase, activate the intra-S-phase checkpoint and induce replication fork slowing and stalling with single-stranded DNA segments coated with replication protein A. Such situation with abnormal replication forks is known as replication stress. SLFN11 irreversibly blocks replication in cells under replication stress, explaining why SLFN11-positive cells are markedly more efficiently killed by DNA-targeting drugs than SLFN11-negative cells. SLFN11 is inactivated in ~50% of cancer cell lines and in a large fraction of tumors, and is linked with the native immune, interferon and T-cells responses, implying the translational relevance of measuring SLFN11 expression as a predictive biomarker of response and resistance in patients. SLFN11 is also a plausible epigenetic target for reactivation by inhibitors of histone deacetylases (HDAC), DNA methyltransferases (DNMT) and EZH2 histone methyltransferase and for combination of these epigenetic inhibitors with DNA-targeting drugs in cells lacking SLFN11 expression. In addition, resistance due to lack of SLFN11 expression in tumors is a potential indication for cell-cycle checkpoint inhibitors in combination with DNA-targeting therapies. [ABSTRACT FROM AUTHOR]

Radiation therapy is a standard treatment for local disease control of solid tumors. Although radiation therapy has significantly improved the overall survival and quality of life of cancer patients, its efficacy has been limited by the development of radiation resistance and the presence of residual disease after therapy, leading to cancer recurrence. Radiation induces cytotoxicity in cancer cells, mainly by causing DNA damage. However, concurrently radiation can also activate multiple protective signaling pathways, such as ataxia telangiectasia mutated/ataxia telangiectasia mutated and Rad3‐related protein, phosphoinositide‐3‐kinase/protein kinase B, extracellular signal‐regulated kinase, and nuclear factor‐κB, which promote cell cycle checkpoint activation, leading to cell cycle arrest/DNA repair and inhibition of apoptosis. Conjointly, these signaling pathways protect cancer cells by reducing the magnitude of radiation‐induced cytotoxicity and promoting radioresistance of cancer cells. Thus, targeting these prosurvival pathways could have great potential for sensitizing cancer cells to radiation therapy. In the present review, we summarize the current literature on the radiation‐activated prosurvival signaling pathways that promote radioresistance. [ABSTRACT FROM AUTHOR]

An important role for the DNA mismatch repair (MMR) pathway in maintaining genomic stability is embodied in its conservation through evolution and the link between loss of MMR function and tumorigenesis. The latter is evident as inheritance of mutations within the major MMR genes give rise to the cancer predisposition condition, Lynch syndrome. Nonetheless, how MMR loss contributes to tumorigenesis is not completely understood. In addition to preventing the accumulation of mutations, MMR also directs cellular responses, such as cell cycle checkpoint or apoptosis activation, to different forms of DNA damage. Understanding this MMR-dependent DNA damage response may provide insight into the full tumor suppressing capabilities of the MMR pathway. Here, we delve into the proposed mechanisms for the MMR-dependent response to DNA damaging agents. We discuss how these pre-clinical findings extend to the clinical treatment of cancers, emphasizing MMR status as a crucial variable in selection of chemotherapeutic regimens. Also, we discuss how loss of the MMR-dependent damage response could promote tumorigenesis via the establishment of a survival advantage to endogenous levels of stress in MMR-deficient cells. [ABSTRACT FROM AUTHOR]

During cell division, the timing of mitosis and cytokinesis must be ordered to ensure that each daughter cell receives a complete, undamaged copy of the genome. In fission yeast, the septation initiation network (SIN) is responsible for this coordination, and a mitotic checkpoint dependent on the E3 ubiquitin ligase Dma1 and the protein kinase CK1 controls SIN signaling to delay cytokinesis when there are errors in mitosis. The participation of kinases and ubiquitin ligases in cell cycle checkpoints that maintain genome integrity is conserved from yeast to human, making fission yeast an excellent model system in which to study checkpoint mechanisms. In this review, we highlight recent advances and remaining questions related to checkpoint regulation, which requires the synchronized modulation of protein ubiquitination, phosphorylation, and subcellular localization. [ABSTRACT FROM AUTHOR]

Maintenance of genome integrity is a key issue for all living organisms. Cells are constantly exposed to DNA damage due to replication or transcription, cellular metabolic activities leading to the production of Reactive Oxygen Species (ROS) or even exposure to DNA damaging agents such as UV light. However, genomes remain extremely stable, thanks to the permanent repair of DNA lesions. One key mechanism contributing to genome stability is the DNA Damage Response (DDR) that activates DNA repair pathways, and in the case of proliferating cells, stops cell division until DNA repair is complete. The signaling mechanisms of the DDR are quite well conserved between organisms including in plants where they have been investigated into detail over the past 20 years. In this review we summarize the acquired knowledge and recent advances regarding the DDR control of cell cycle progression. Studying the plant DDR is particularly interesting because of their mode of development and lifestyle. Indeed, plants develop largely post-embryonically, and form new organs through the activity of meristems in which cells retain the ability to proliferate. In addition, they are sessile organisms that are permanently exposed to adverse conditions that could potentially induce DNA damage in all cell types including meristems. In the second part of the review we discuss the recent findings connecting the plant DDR to responses to biotic and abiotic stresses. [ABSTRACT FROM AUTHOR]

Chromatin is a significant barrier to many DNA damage response (DDR) factors, such as DNA repair enzymes, that process DNA lesions to reduce mutations and prevent cell death; yet, paradoxically, chromatin also has a critical role in many signaling pathways that regulate the DDR. The primary level of DNA packaging in chromatin is the nucleosome core particle (NCP), consisting of DNA wrapped around an octamer of the core histones H2A, H2B, H3 and H4. Here, we review recent studies characterizing how the packaging of DNA into nucleosomes modulates the activity of the base excision repair (BER) pathway and dictates BER subpathway choice. We also review new evidence indicating that the histone amino-terminal tails coordinately regulate multiple DDR pathways during the repair of alkylation damage in the budding yeast Saccharomyces cerevisiae. [ABSTRACT FROM AUTHOR]

Objectives: Immune checkpoint therapy has been promising in renal cell carcinoma, but no validated clinically relevant biomarkers exist. Metastatic deposits may have discordant biomarker expression.Methods: Fifty matched pairs of primary and metastatic kidney tumors were evaluated via immunohistochemistry for immune checkpoint proteins PD-1, PD-L1, and PD-L2 and the T-cell and macrophage surface markers CD3, FOXP3, and CD163. Semiquantitative scores incorporating prevalence of both tumor and nontumor labeling were compared between metastatic and primary kidney tumor specimens.Results: A large minority of patients had discordant expression of PD-1 (31.2%), PD-L1 (22.5%), or PD-L2 (21.5%) between primary and metastatic sites. The expression of the novel marker PD-L2 correlated with both PD-1 (r = 0.47, P = .02) and PD-L1 (r = 0.67, P < .001) in metastatic deposits.Conclusions: This study demonstrates that renal clear cell carcinoma primary tumors and metastatic deposits have some discordance in the expression of PD-L1, PD-1, and PD-L2. [ABSTRACT FROM AUTHOR]