DNA Repair最新文献

{"title":"The fragile centromere","authors":"Simona Giunta","doi":"10.1016/j.dnarep.2026.103973","DOIUrl":"10.1016/j.dnarep.2026.103973","url":null,"abstract":"<div><div>Human centromeres are long stretches of repetitive DNA located at the primary constriction of human chromosomes. Specialized nucleosomes containing the histone H3 variant, CENP-A, serve as basal template for the assembly of the human kinetochore for faithful chromosome segregation. Recent functional studies, long-read sequencing and new reference genomes have finally enabled the exploration of these complex sequences. For the first time, the mechanisms underlying the origin, evolution, and preservation of centromeric repeats are coming into view. The dual dynamics of preservation and rapid evolution are encapsulated by our recent discovery of a stable centromere architecture despite underlying divergence, implying strong selection to maintain the overall repeat structure while tolerating high rates of sequence variation across species, individuals, and between maternal and paternal haplotypes in each person. Here, I review the latest technological and conceptual advances that are fueling exploration of human centromere organization and maintenance, including stabilizing and destabilizing forces within the kinetochore binding site. Intrinsic propensity to secondary structures synergizing with the sudden drop in methylation at the functional locus can, during DNA-based transactions, cause breaks, with ensuing rearrangements and chromosomal arm-level events that perturb overall genome integrity. The (epi)genetic information ‘written’ within centromeres reveals the footprint of DNA repair pathways and mutational processes. I propose recombination-driven repeat homogenization to be a form of antagonistic pleiotropy, where array uniformity benefits kinetochore assembly and meiotic transmission at the cost of dynamic somatic changes, chromosomal rearrangements and genome instability that can drive cancer etiology.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"167 ","pages":"Article 103973"},"PeriodicalIF":3.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149303212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DNA polymerase λ: Emerging from the shadows after a quarter of a century","authors":"N.I. Rechkunova,&nbsp;N.A. Lebedeva,&nbsp;O.I. Lavrik","doi":"10.1016/j.dnarep.2026.103978","DOIUrl":"10.1016/j.dnarep.2026.103978","url":null,"abstract":"<div><div>DNA polymerase λ (Pol λ) belongs to the X family of DNA polymerases, along with DNA polymerases β (Pol β) and μ (Pol μ), and terminal deoxynucleotidyl transferase (TdT). Since its discovery in 2000, Pol λ has been the subject of intensive study, which has established its structural and biochemical characteristics and determined main enzymatic activities and biological functions. Although the intensity of research on this enzyme has decreased in recent years, interest in it has persisted, because its precise role in the cellular response to DNA damage remains to be fully elucidated. Some important findings on the involvement of Pol λ in DNA repair have been obtained quite recently, specifically, on the interaction with the proteins of non-homologues end joining and base excision repair pathways regulating its activity. In this review, we discuss the properties of Pol λ—both common for all X-family polymerases and unique to this enzyme—with particular emphasis on its roles in DNA repair and impact in resistance to genotoxic stress.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"167 ","pages":"Article 103978"},"PeriodicalIF":3.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149345188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genomic characteristics and immunotherapy benefit in MSI-H/dMMR lung cancer: Insights from comparative analyses of Chinese and Western cohorts","authors":"Chao Zhou,&nbsp;Chengqi Sun,&nbsp;Hui Jin,&nbsp;Wentao Li,&nbsp;Chaoxun Deng","doi":"10.1016/j.dnarep.2026.103970","DOIUrl":"10.1016/j.dnarep.2026.103970","url":null,"abstract":"<div><h3>Introduction</h3><div>Microsatellite instability (MSI) is a pivotal pan-cancer biomarker for immune checkpoint inhibitor (ICI) therapy. However, due to the low frequency of MSI-high (MSI-H) in lung cancer (LC), the genetic characteristics and prognosis of this subgroup were rarely reported.</div></div><div><h3>Methods</h3><div>A total of 4539 Chinese LC patients were screened for microsatellite instability-high (MSI-H)/deficient DNA mismatch repair (dMMR) status. Of these, 344 patients with available detailed clinical and genomic data were further analyzed to assess clinicopathologic correlates and genomic differences compared to 1053 samples from The Cancer Genome Atlas (TCGA). Comparative analyses were performed between MSI-H/dMMR and microsatellite stable (MSS)/proficient mismatch repair (pMMR) groups, as well as between the Chinese and TCGA dMMR cohorts. Additionally, we performed a systematic literature review to evaluate clinical outcomes.</div></div><div><h3>Results</h3><div>We observed an overall MSI-H/dMMR prevalence of 1.08% in Chinese patients. While the rate in non-small cell lung cancer (NSCLC) was 1.94%, the phenotype was predominantly observed in lung squamous cell carcinoma (LUSC, 3.81%), which was approximately four-fold higher than that in lung adenocarcinoma (LUAD, 0.89%). TCGA data showed similar LUSC predominance (1.85% vs. 1.41% in LUAD). MSI-H/dMMR status were correlated with younger age, early-stage, and non-metastatic disease. Chinese MSI-H/dMMR LC samples showed frequent <em>TP53</em>, <em>EGFR</em>, and <em>BRCA2</em> mutations, enriched indel mutations and C&gt;T transitions. TCGA MSI-H/dMMR tumors had higher <em>TP53</em> (82.4% vs. 52.3%) and lower <em>EGFR</em> mutations than Chinese patients. A literature review of 16 MSI-H/dMMR patients suggests prolonged progression-free survival (PFS) with ICI regimens.</div></div><div><h3>Conclusions</h3><div>MSI-H/dMMR LC exhibits distinct clinicogenomic features between Chinese vs. TCGA population, with histotype- and cohort-specific mutational landscapes. These findings inform MMR-driven tumor biology and ethnic-dependent therapeutic strategies.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"167 ","pages":"Article 103970"},"PeriodicalIF":3.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149290649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RAD54 suppresses theta-mediated end joining in non-homologous end joining-compromised FaDu tumor cells","authors":"Gerarda van de Kamp,&nbsp;Joost Schimmel,&nbsp;Tim Heemskerk,&nbsp;Anna Hegger,&nbsp;Marianne Kersten,&nbsp;Nicole Verkaik,&nbsp;Roland Kanaar,&nbsp;Marcel Tijsterman,&nbsp;Jeroen Essers","doi":"10.1016/j.dnarep.2026.103975","DOIUrl":"10.1016/j.dnarep.2026.103975","url":null,"abstract":"<div><div>Cells maintain genomic integrity through multiple DNA repair pathways. DNA double strand breaks (DSBs) are particularly hazardous, leading to cell death or genomic instability if not properly repaired. Three major DSBs repair pathways exist: non-homologous end joining (NHEJ), homologous recombination (HR), and theta-mediated end joining (TMEJ). However, it is unclear whether tumor cells can efficiently engage all three pathways in response to ionizing radiation (IR). We investigated DSB repair in FaDu human head and neck squamous cell carcinoma cells by generating knockout cells deficient in NHEJ protein DNA Ligase 4 (LIG4), HR protein RAD54, or TMEJ protein Polymerase Theta (Pol Ɵ), respectively and assessed IR sensitivity and Cas9-induced mutational signatures. NHEJ-deficient cells displayed increased IR sensitivity and delayed 53BP1 foci resolution, revealing strong reliance on NHEJ for DSB repair. RAD54 deficient cells showed no increased IR sensitivity, but TMEJ-mediated mutations increased, especially when NHEJ was inactive. These results indicate that RAD54 channels repair toward high-fidelity HR while suppressing mutagenic TMEJ. This study underscores the critical role of NHEJ in DSB repair and provides insights into the compensatory use of mutagenic repair pathways in human tumor cells when HR is compromised.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"167 ","pages":"Article 103975"},"PeriodicalIF":3.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149328933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low-blast SF3B1 myelodysplastic neoplasm shows reduced tolerance to splice-site variants in translesion DNA repair genes","authors":"Ronald Feitosa Pinheiro,&nbsp;Roberta Taiane Germano de Oliveira,&nbsp;Renan Victor Brito Aguiar Parente,&nbsp;Antonio Wesley Araújo dos Santos,&nbsp;Carlos Leonardo de Aragão Araújo,&nbsp;Edilson Diogenes Pinheiro Junior,&nbsp;Yuri Vasconcelos Pinheiro","doi":"10.1016/j.dnarep.2026.103979","DOIUrl":"10.1016/j.dnarep.2026.103979","url":null,"abstract":"<div><div>Myelodysplastic neoplasm (MDS) is the most common primary bone marrow malignancy, usually presenting refractory cytopenias. Although mutations occur in up to 94% of cases, splicing changes in genes supporting chromosomal stability are poorly defined. We used next-generation sequencing (NGS) to identify canonical splice-site variants in translesion synthesis (TLS) polymerase genes (<em>POLI, POLL, POLM, POLN, POLQ, REV1, REV3L,</em> and <em>POLH</em>) in two MDS subgroups: MDS with increased blasts (MDS-IB) and low-blast MDS with <em>SF3B1</em> mutation (MDS-<em>SF3B1</em>). Variant frequencies differed: <em>POLI</em> carried several variants, while <em>REV3L</em> and <em>POLH</em> displayed none, apart from the MDS cohort. Splice-site variants were more frequent in MDS-IB (likelihood ratio up to 9.6 for <em>POLI</em>), despite MDS-SF3B1 being typically associated with splicing dysfunction. Furthermore, despite harboring a mutation in a core splicing factor (<em>SF3B1</em>), MDS-<em>SF3B1</em> cases showed fewer splice variants among all TLS DNA-repair genes (mean 1,93 ×0,69; p &lt; 0,005). Overall, We identified only 11 unique splice-site variants across the TLS spectrum, which supports the conclusion that TLS polymerase genes are highly conserved in humans.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"167 ","pages":"Article 103979"},"PeriodicalIF":3.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149345189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Catalytic efficiency of predicted deleterious missense variants of human DNA dioxygenase ABH2","authors":"Viktoriia V. Sagalakova,&nbsp;Anastasiia T. Davletgildeeva,&nbsp;Viktoriia A. Kolesnikova,&nbsp;Nikita A. Kuznetsov","doi":"10.1016/j.dnarep.2026.103977","DOIUrl":"10.1016/j.dnarep.2026.103977","url":null,"abstract":"<div><div>Human DNA dioxygenase ABH2 is a key Fe(II)/α-ketoglutarate-dependent enzyme that removes a broad range of cytotoxic alkylated lesions, including <em>N</em> ¹ -methyladenine (m¹A) and <em>N</em> ³ -methylcytosine (m³C), from double-stranded DNA, thereby supporting genome stability. Naturally occurring missense single nucleotide variants (SNVs) in the ABH2 gene can modulate its catalytic properties and, consequently, the efficiency of direct DNA repair. In this study, we functionally characterized eight ABH2 variants featuring SNVs-associated substitutions G103R, S125L, S188F, F195S, M226T, R248Q, R248W, or T252I, that had been previously (Davletgildeeva et al., 2025) classified as potentially deleterious by multiple prediction algorithms. We quantified kinetic parameters of the corresponding ABH2 variants toward double-stranded DNA substrates containing either m¹A or m³C and compared their catalytic efficiency to that of the wild-type enzyme. For most of the variants, the negative prognosis was justified, as the introduced substitutions, while maintaining the general architecture of the protein globule and having insignificant differences in thermal stability, led to a decrease (G103R, S188F, T252I, and, to a lesser extent, S125L) or even complete loss (R248Q and R248W) of the catalytic activity of the ABH2 enzyme toward both tested damaged nucleobases. At the same time, M226T and F195S variants demonstrated an increase in activity of the enzyme toward m³C, thus contradicting the obtained negative prognosis. Our findings show that naturally occurring ABH2 missense variants can differentially alter the repair efficiency of m¹A and m³C lesions in double-stranded DNA, ranging from partial to complete loss or lesion-selective enhancement of catalytic activity. Structural analysis suggests that these functional effects arise from disruption of local interactions and/or changes in conformational flexibility required to form a catalytically competent enzyme–DNA complex. Overall, these results delineate a diverse functional landscape of naturally occurring ABH2 missense variants and provide a quantitative framework for understanding how sequence variation shapes the enzyme’s DNA repair capacity.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"167 ","pages":"Article 103977"},"PeriodicalIF":3.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149303226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential roles of translesion synthesis polymerases eta and iota in UV-induced mutagenesis of mouse skin cells and tissues","authors":"Yasutaka Sakurai,&nbsp;Masayuki Yokoi,&nbsp;Taiki Sugimoto,&nbsp;Tsuyoshi Ohkumo,&nbsp;Daiki Morita,&nbsp;Tetsuya Tsukamoto,&nbsp;Tsukasa Oda,&nbsp;Min Gi,&nbsp;Anna Kakehashi,&nbsp;Takayuki Yamashita,&nbsp;Hideki Wanibuchi,&nbsp;Masae Tatematsu,&nbsp;Fumio Hanaoka","doi":"10.1016/j.dnarep.2026.103974","DOIUrl":"10.1016/j.dnarep.2026.103974","url":null,"abstract":"<div><div>Xeroderma pigmentosum variant (XP-V) is a human genetic disorder characterized by an increased risk of skin cancer following ultraviolet (UV) exposure and caused by a deficiency in DNA polymerase eta (Polη), a specialized enzyme involved in translesion DNA synthesis (TLS). Polι, a paralog of Polη, exhibits TLS activity on UV-induced DNA lesions <em>in vitro</em>; however, its <em>in vivo</em> function remains unclear. We previously reported that Polη- and Polι-deficient mice exposed to UV irradiation developed epithelial and mesenchymal skin tumors, respectively. To elucidate how Polη and Polι suppress UV-induced mutagenesis and tumorigenesis in distinct skin tissues, we analyzed <em>Trp53</em> mutations in UV-induced skin tumors and established cell lines of mouse epidermal keratinocytes (MKCs) and dermal fibroblasts (MDFs) from wild-type and Polη-deficient mice. Although wild-type MKCs were more resistant to UV irradiation than wild-type MDFs, Polη-deficient MKCs and MDFs exhibited similar UV sensitivity. Polη was rapidly degraded in MDFs following UV irradiation, whereas Polι remained stable. Moreover, Polη deficiency increased the frequency of UV-induced mutations in both MKCs and MDFs; however, this effect was more pronounced in MKCs. Polι knockdown had no substantial effect on UV sensitivity, whereas Polι overexpression reduced the mutation frequency in Polη-deficient MDFs. These findings suggest that Polη and Polι have distinct roles in the UV response and that UV-induced degradation of Polη in MDFs may promote the participation of Polι and alternative polymerases in TLS, thereby contributing to tissue-specific suppression of UV-induced mutagenesis and tumorigenesis.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"167 ","pages":"Article 103974"},"PeriodicalIF":3.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149328931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Off-target suppression of cell proliferation by commercially available DNA2 inhibitors","authors":"Oluwatobiloba Awolalu,&nbsp;Jessica J.R. Hudson,&nbsp;Ulrich Rass","doi":"10.1016/j.dnarep.2026.103972","DOIUrl":"10.1016/j.dnarep.2026.103972","url":null,"abstract":"<div><div>The disease-associated DNA2 nuclease-helicase is critical for the proper processing of stalled DNA replication forks (RFs). DNA2 inhibition therefore has the potential to cause synthetic lethality in cancer cells in which DNA replication stress and RF stalling are prevalent. Several small molecule biochemical inhibitors of DNA2 have been identified. 4-hydroxy-8-nitroquinoline-3-carboxylic acid, known as DNA2 inhibitor C5, has been widely adopted as a tool compound to test the anti-cancer potential of targeting DNA2 in cellular models, and to study the dependence of molecular processes on DNA2 in cells. Here, we show that C5 treatment does not phenocopy DNA2 loss or inactivation in cells. Independently of DNA2, C5, and its derivative d16, strongly inhibit DNA synthesis in S phase of the cell cycle, revealing off-target anti-proliferative activity. Finally, C5 and d16 are unable to inhibit helicase-dependent single-stranded DNA (ssDNA) accumulations generated by a nuclease-dead version of DNA2. These data show that commonly used compounds fail to effectively inhibit DNA2 in cells and highlight potential caveats in the interpretation of published cellular data obtained with C5 and d16. Moreover, our experimental workflow provides an in cellulo analysis pipeline suitable for identifying biologically active DNA2 inhibitors as a tool for fundamental research and validation of DNA2 as an emerging anti-cancer therapeutic target.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"167 ","pages":"Article 103972"},"PeriodicalIF":3.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149328932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repair of replication-born DNA lesions before and during mitosis","authors":"H. Rudolf de Boer,&nbsp;Marcel A.T.M. van Vugt","doi":"10.1016/j.dnarep.2026.103976","DOIUrl":"10.1016/j.dnarep.2026.103976","url":null,"abstract":"<div><div>Proliferation of cells involves the accurate duplication of the genome during S-phase. This highly complex process constantly faces physiological challenges. Specifically, the DNA template can harbor various barriers that block replication fork progression, including protein crosslinks, DNA crosslinks, or the transcription machinery that is active at the same template. These barriers lead to stalled replication forks that need to be resolved to ensure complete DNA replication. Alternatively, DNA damage tolerance pathways need to be activated to continue DNA replication. To ensure genome integrity in the face of these challenges, various DNA repair mechanisms exist that can repair replication-born DNA lesions during DNA replication, while post-replicative DNA repair participates to resolve replication-born DNA lesions before cells enter mitosis. However, we increasingly realize that replication-born DNA lesions frequently remain unresolved at the point that cells enter mitosis. To ensure correct chromosome segregation and genome integrity in daughter cells, these remaining DNA lesions need to be processed during mitosis. In this review, we summarize the cellular conditions that lead to mitotic DNA lesions and discuss recent insights into the mechanisms that resolve replication-born DNA lesions during mitosis.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"167 ","pages":"Article 103976"},"PeriodicalIF":3.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149345190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Features of cancer cell metabolism linked to DNA repair mechanisms","authors":"Regina Mikheeva,&nbsp;Pavel Leonov,&nbsp;Maksim Koryukov,&nbsp;Ekaterina Ruleva,&nbsp;Xue-Song Liu,&nbsp;Andrey Kechin","doi":"10.1016/j.dnarep.2026.103969","DOIUrl":"10.1016/j.dnarep.2026.103969","url":null,"abstract":"<div><div>Metabolic pathways in tumor cells can diverge significantly from the canonical pathways described for healthy tissues and cells. Although they involve the same proteins and substrate molecules, differences in metabolite concentrations, the skipping of only a few pathway participants, and alterations in downstream signaling processes and post-translational modifications of enzymes can lead to substantially altered cell morphology and function. In recent years, several novel and unexpected protein modifications caused by impaired tumor cell metabolism, as well as unusual roles of certain metabolic products, have been discovered. By integrating these new findings with current knowledge of DNA repair mechanisms, this review aims to discuss the latest discoveries regarding the peculiarities of tumor cell metabolism. This review examines the local supply of ATP, NAD⁺, acetyl-CoA and deoxyribonucleoside triphosphates at DNA damage sites. It also covers metabolite-driven modifications of repair proteins, with a focus on lysine lactylation. The discussion then shifts to the tumor microenvironment, where hypoxia, acidosis and nutrient limitation alter repair pathway choice. Finally, it considers the therapeutic window for targeting the metabolic enzymes involved. Such insights may prove valuable for future targeted drug development. We also argue that the subcellular compartmentalization and post-translational regulation described here limit how far metabolic inferences drawn from transcriptomes can be trusted. Metabolic pathways should therefore not be treated as distinct, static entities for analysis, since doing so may lead to missed opportunities to identify novel biomarkers or drug targets. The variability of metabolism in tumor cells is much greater than previously thought.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"167 ","pages":"Article 103969"},"PeriodicalIF":3.2,"publicationDate":"2026-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149279013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}