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Mammalian polynucleotide kinase 3'-phosphatase (PNKP), a DNA end-processing enzyme with 3'-phosphatase and 5'-kinase activities, is involved in multiple DNA repair pathways, including base excision (BER), single-strand break (SSBR), and double-strand break repair (DSBR). However, little is known as to how PNKP functions in such diverse repair processes. Here we report that PNKP is acetylated at K142 (AcK142) by p300 constitutively but at K226 (AcK226) by CBP, only after DSB induction. Co-immunoprecipitation analysis using AcK142 or AcK226 PNKP-specific antibodies showed that AcK142-PNKP associates only with BER/SSBR, and AcK226 PNKP with DSBR proteins. Despite the modest effect of acetylation on PNKP's enzymatic activity in vitro, cells expressing non-acetylable PNKP (K142R or K226R) accumulated DNA damage in transcribed genes. Intriguingly, in striatal neuronal cells of a Huntington's Disease (HD)-based mouse model, K142, but not K226, was acetylated. This is consistent with the reported degradation of CBP, but not p300, in HD cells. Moreover, transcribed genomes of HD cells progressively accumulated DSBs. Chromatin-immunoprecipitation analysis demonstrated the association of Ac-PNKP with the transcribed genes, consistent with PNKP's role in transcription-coupled repair. Thus, our findings demonstrate that acetylation at two lysine residues, located in different domains of PNKP, regulates its distinct role in BER/SSBR versus DSBR.

SARS-CoV-2 infection-induced aggravation of host innate immune response not only causes tissue damage and multiorgan failure in COVID-19 patients but also induces host genome damage and activates DNA damage response pathways. To test whether the compromised DNA repair capacity of individuals modulates the severity of COVID-19 infection, we analyze DNA repair gene expression in publicly available patient datasets and observe a lower level of the DNA glycosylase NEIL2 in the lungs of severely infected COVID-19 patients. This observation of lower NEIL2 levels is further validated in infected patients, hamsters and ACE2 receptor-expressing human A549 (A549-ACE2) cells. Furthermore, delivery of recombinant NEIL2 in A549-ACE2 cells shows decreased expression of proinflammatory genes and viral E-gene, as well as lowers the yield of viral progeny compared to mock-treated cells. Mechanistically, NEIL2 cooperatively binds to the 5'-UTR of SARS-CoV-2 genomic RNA to block viral protein synthesis. Collectively, these data strongly suggest that the maintenance of basal NEIL2 levels is critical for the protective response of hosts to viral infection and disease.

Compromised DNA repair capacity of individuals could play a critical role in the severity of SARS-CoV-2 infection-induced COVID-19. We therefore analyzed the expression of DNA repair genes in publicly available transcriptomic datasets of COVID-19 patients and found that the level of NEIL2, an oxidized base specific mammalian DNA glycosylase, is particularly low in the lungs of COVID-19 patients displaying severe symptoms. Downregulation of pulmonary NEIL2 in CoV-2-permissive animals and postmortem COVID-19 patients validated these results. To investigate the potential roles of NEIL2 in CoV-2 pathogenesis, we infected Neil2-null (Neil2-/-) mice with a mouse-adapted CoV-2 strain and found that Neil2-/- mice suffered more severe viral infection concomitant with increased expression of proinflammatory genes, which resulted in an enhanced mortality rate of 80%, up from 20% for the age matched Neil2+/+ cohorts. We also found that infected animals accumulated a significant amount of damage in their lung DNA. Surprisingly, recombinant NEIL2 delivered into permissive A549-ACE2 cells significantly decreased viral replication. Toward better understanding the mechanistic basis of how NEIL2 plays such a protective role against CoV-2 infection, we determined that NEIL2 specifically binds to the 5'-UTR of SARS-CoV-2 genomic RNA and blocks protein synthesis. Together, our data suggest that NEIL2 plays a previously unidentified role in regulating CoV-2-induced pathogenesis, via inhibiting viral replication and preventing exacerbated proinflammatory responses, and also via its well-established role of repairing host genome damage.

Societal Impact Statement: Unraveling the genetic intricacies and evolutionary history of Asian Hickories through advanced genome sequencing gives valuable insights into their ecological adaptations. Understanding the impact of historical dynamics, climate fluctuations, and geographical barriers on Asian hickories not only contributes to scientific knowledge but also empowers policymakers with evidence‐based decisions and guides conservationists in their efforts to protect vulnerable species. The identification of potential habitats, especially for the endangered Carya kweichowensis, offers a promising avenue for targeted conservation efforts, aligning with global initiatives to preserve Earth's precious biodiversity, but also ensures the conservation of a vital genetic reservoir for nut‐bearing economic tree species. Summary: Biogeographic characteristics of disjunct distribution play a vital role in plant geography and the endangered mechanism. The whole genome resequencing provides an opportunity to study the genetic relationship, population diffusion, and floristic evolution of disjunctive‐distribution flora. Based on the SNPs (single nucleotide polymorphisms) data generated by the whole genome deep resequencing of five EA (Eastern Asian) Carya species, we constructed the phylogenetic tree, genetic structure, and species distribution modeling to clarify the phylogenetic relationships and to predict the potential distribution area of EA Carya. Phylogenetic analysis of Carya revealed two distinct clades, separating EA Carya from NA (North America) Carya. C. kweichowensis, an endangered species, showed the lowest nucleotide diversity and the earliest divergence among studied EA Carya species. Species distribution modeling predicted suitable habitats for five EA Carya species, revealing the potential distribution of endangered C. kweichowensis. Importantly, minimal spatial overlap was observed among distribution regions of EA Carya species during different time periods. The uneven regional distribution of EA Carya is believed to be a consequence of Quaternary climate fluctuations, mountain barriers hindering species dispersal, and the limited cold tolerance of these trees. EA Carya highlights the significant role of climate and geological changes in their regional distribution and migration routes in Asia. Furthermore, the discovery of potential habitats offers a promising avenue for the conservation of C. kweichowensis. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV), along with other prominent respiratory RNA viruses such as influenza and SARS-CoV-2, significantly contributes to the global incidence of respiratory tract infections. These pathogens induce the production of reactive oxygen species (ROS), which play a crucial role in the onset and progression of respiratory diseases. However, the mechanisms by which viral RNA manages ROS-induced base oxidation remain poorly understood. Here, we reveal that 8-oxo-7,8-dihydroguanine (8-oxoGua) is not merely an incidental byproduct of ROS activity but serves as a strategic adaptation of RSV RNA to maintain genetic fidelity by hijacking the 8-oxoguanine DNA glycosylase 1 (OGG1). Through RNA immunoprecipitation and next-generation sequencing, we discovered that OGG1 binding sites are predominantly found in the RSV antigenome, especially within guanine-rich sequences. Further investigation revealed that viral ribonucleoprotein complexes specifically exploit OGG1. Importantly, inhibiting OGG1's ability to recognize 8-oxoGua significantly decreases RSV progeny production. Our results underscore the viral replication machinery's adaptation to oxidative challenges, suggesting that inhibiting OGG1's reading function could be a novel strategy for antiviral intervention. Author summary: Respiratory tract infections caused by RSV present a significant public health concern, especially affecting infants and the elderly. Effective antiviral strategies are urgently needed against this non-segmented, negative-sense RNA virus of the Pneumoviridae family. Our research reveals how RSV maintains replication fitness despite oxidative damage, a common exacerbator of respiratory conditions. We have identified a mechanism where RSV preserves its genome integrity under oxidative stress using the DNA repair enzyme OGG1. This enzyme ensures that the viral RNA accurately pairs 8-oxoGua with cytosine, crucial for maintaining the fidelity of the viral genome. Targeting the interplay between OGG1 and RSV RNA offers a promising approach for developing novel antiviral treatments, potentially countering the virus's evolutionary adaptations. [ABSTRACT FROM AUTHOR]

BACKGROUND: Echinochloa crus‐galli is the most troublesome and widespread weed of most rice‐growing regions of the world. Cyhalofop‐butyl, a herbicide within the acetyl‐CoA carboxylase (ACCase) chemical group, has been extensively used to control barnyardgrass in rice. The repeated exposure to cyhalofop‐butyl has led to resistance evolution in E. crus‐galli populations. RESULTS: In this study, we identified a population of E. crus‐galli (R‐HN) in a rice field in Hunan, China, that developed resistance to cyhalofop‐butyl at 4.49‐fold the recommended field dose. No known target mutation was detected in the ACCase gene of the R‐HN population by ACCase sequencing compared to sensitive populations. Both cytochrome P450 (CYP450) and glutathione S‐transferase (GST) inhibitors could not significantly reverse the resistance to cyhalofop‐butyl. The nontarget‐site resistance (NTSR) mechanism was investigated by transcriptome sequencing. Validation of the screened candidate genes by quantitative real‐time (qRT)‐PCR revealed that six glycosyltransferases (GTs) and four ATP‐binding cassette (ABC) transporter genes were consistently upregulated in the R‐HN population. Five GTs and one ABC transporter genes were constitutively upregulated after cyhalofop‐butyl treatment in the R‐HN population. Molecular docking results showed that the significant binding energy of GT79, GT75L6 and GT74E among all candidate genes. CONCLUSION: Thus, the GT genes appear to be directly implicated in NTSR to cyhalofop‐butyl in the R‐HN populations through metabolic enhancement, but their functional characterization needs to be studied. © 2024 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Continuous and exclusive use of fenoxaprop-P-ethyl has resulted in serious resistance in Beckmannia syzigachne. Isoproturon, a photosystem II inhibitor, is very frequently used in wheat fields, and there are currently few reports about isoproturon resistance in B. syzigachne. However, excessive use of isoproturon is detrimental to the ecological environment. Therefore, adding additives is a good choice to enhance the effect of isoproturon and reduce its usage. Jijian is a non-ionic and polyhydric alcohol surfactant. Greenhouse whole-plant bioassay results showed that 0.05% (v/v) of Jijian + 600 g ai ha−1 of isoproturon achieved the best synergistic effect on controlling fenoxaprop-P-ethyl-resistant B. syzigachne. Jijian significantly reduced the surface tension and contact angle of the isoproturon solution by 15.8 mN m−1 and 33.2°, respectively, and significantly increased the expanded diameter and maximum retention by 0.92 mm and 8.39 mg cm−2 respectively. In conclusion, Jijian had a synergistic effect on isoproturon in the control of fenoxaprop-P-ethyl-resistant B. syzigachne and Jijian may achieve the synergistic effect by changing the physical properties of isoproturon solution on weeds. [ABSTRACT FROM AUTHOR]

Summary: Background: There is limited evidence on the associations of dietary factors and patterns with risk of later‐onset ulcerative colitis (UC) in Chinese adults. Aims: To investigate the associations of dietary factors and patterns with risk of later‐onset UC in Chinese. Methods: The prospective China Kadoorie Biobank cohort study recruited 512,726 participants aged 30–79. Dietary habits were assessed using food frequency questionnaires. Dietary patterns were derived by factor analysis with a principal component method. Cox regression analysis was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: During a median follow‐up of 12.1 years, 312 cases of newly diagnosed UC were documented (median age of diagnosis 60.1 years). Egg consumption was associated with higher risk of UC (HR for daily vs. never or rarely: 2.29 [95% CI: 1.26–4.16]), while spicy food consumption was inversely associated with risk of UC (HR: 0.63 [0.45–0.88]). The traditional northern dietary pattern, characterised by high intake of wheat and low intake of rice, was associated with higher risk of UC (HR for highest vs. lowest quartile of score: 2.79 [1.93–4.05]). The modern dietary pattern, characterised by high intake of animal‐origin foods and fruits, was associated with higher risk of UC (HR: 2.48 [1.63–3.78]). Population attributable fraction was 13.04% (7.71%–19.11%) for daily/almost daily consumption of eggs and 9.87% (1.94%–18.22%) for never/rarely consumption of spicy food. Conclusions: The findings highlight the importance of evaluating dietary factors and patterns in the primary prevention of later‐onset UC in Chinese adults. [ABSTRACT FROM AUTHOR]

Simple Summary: OGG1-enabled NFκB activity can promote cancer progression via a number of key mechanisms that include phenotypic transitions of cancer and stromal cells, expression and secretion of molecules that modulate innate immunity, and alteration of the vascular network. Under oxidative stress, the supraphysiological levels of nongenotoxic 8-oxoGua, along with redox inactivation of OGG1 via cysteine oxidation and potential dimerization, provide multiple interfaces with redox-activated/modulated NFκB and other transacting factors, including Myc. This promotes not only cell proliferation, the expression of innate immune genes, and angiogenesis but also the metastatic capability of cells involving the expression of epithelial–mesenchymal transition genes. Mounting evidence supports the idea that increased levels of oxidative stress play a crucial role in the onset and progression of solid and lymphoid malignancies. This is achieved by gaining mutations and by activating signaling pathways that promote cell survival, cell proliferation, and resistance to treatment modalities. 8-oxoguanine glycosylase 1 (OGG1), which was initially identified as the enzyme that catalyzes the first step in the DNA base excision repair pathway, is now also recognized as a modulator of gene expression. What is important for cancer is that OGG1 acts as a modulator of NFκB-driven gene expression. Specifically, oxidant stress in the cell transiently halts enzymatic activity of substrate-bound OGG1. The stalled OGG1 facilitates DNA binding of transactivators, such as NFκB to their cognate sites, enabling the expression of cytokines and chemokines, with ensuing recruitment of inflammatory cells. Recently, we highlighted chief aspects of OGG1 involvement in regulation of gene expression, which hold significance in lung cancer development. However, OGG1 has also been implicated in the molecular underpinning of acute myeloid leukemia. This review analyzes and discusses how these cells adapt through redox-modulated intricate connections, via interaction of OGG1 with NFκB, which provides malignant cells with alternative molecular pathways to transform their microenvironment, enabling adjustment, promoting cell proliferation, metastasis, and evading killing by therapeutic agents. [ABSTRACT FROM AUTHOR]