DNA Repair最新文献

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DNA repair at the crossroads of tumor immunogenicity and cancer therapy: Harnessing innate and adaptive immune pathways for improved therapeutic outcomes DNA修复在肿瘤免疫原性和癌症治疗的十字路口：利用先天和适应性免疫途径改善治疗效果

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-07-22 DOI: 10.1016/j.dnarep.2025.103874

Zhanfeng Liang , Yangrui Xu , Chuan-Yuan Li

Immunotherapy has revolutionized cancer treatment, particularly with immune checkpoint inhibitors (ICIs), which harness the immune system to achieve durable antitumor responses. DNA repair pathways, essential for maintaining genomic stability, play a complex role in cancer. While functional DNA repair prevents tumorigenesis, deficiencies in pathways such as homologous recombination (HR), mismatch repair (MMR), and non-homologous end joining (NHEJ) can amplify tumor immunogenicity. These deficiencies increase tumor mutational burden, generate neoantigens, and activate innate immune sensors like cGAS–STING and RIG-I/MDA5-MAVS. Therapies such as radiotherapy and chemotherapy can enhance these effects by inducing DNA damage and de-repressing endogenous retroviral elements, creating a "viral mimicry" state that promotes immune recognition. Thus, combining DNA repair inhibitors with cytotoxic therapies and immunotherapy has emerged as a promising strategy to enhance antitumor immunity. This review highlights mechanisms by which DNA repair defects and genotoxic stress activate innate immunity, improve antigen presentation, and foster T-cell activation. Emerging approaches integrating PARP and ATM/ATR inhibitors with ICIs, STING agonists, and cancer vaccines offer potential to overcome immune resistance. Personalized combinations tailored to tumor-specific DNA repair and immune profiles hold promises for transforming cancer treatment, with ongoing research aimed at optimizing therapeutic efficacy while minimizing toxicity.

免疫疗法已经彻底改变了癌症治疗，特别是免疫检查点抑制剂（ICIs），它利用免疫系统实现持久的抗肿瘤反应。DNA修复途径对维持基因组稳定性至关重要，在癌症中发挥着复杂的作用。虽然功能性DNA修复可以阻止肿瘤发生，但同源重组（HR）、错配修复（MMR）和非同源末端连接（NHEJ）等途径的缺陷可以增强肿瘤的免疫原性。这些缺陷增加肿瘤突变负担，产生新抗原，并激活先天免疫传感器，如cGAS-STING和RIG-I/MDA5-MAVS。放疗和化疗等疗法可以通过诱导DNA损伤和抑制内源性逆转录病毒元素来增强这些效果，从而产生一种促进免疫识别的“病毒模仿”状态。因此，将DNA修复抑制剂与细胞毒性疗法和免疫疗法相结合已成为增强抗肿瘤免疫的一种有希望的策略。本文综述了DNA修复缺陷和基因毒性应激激活先天免疫、改善抗原呈递和促进t细胞活化的机制。将PARP和ATM/ATR抑制剂与ICIs、STING激动剂和癌症疫苗结合的新方法提供了克服免疫耐药性的潜力。针对肿瘤特异性DNA修复和免疫图谱量身定制的个性化组合有望改变癌症治疗，目前正在进行的研究旨在优化治疗效果，同时将毒性降到最低。

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引用次数: 0

Multiple functions of PARP1 in the repair of DNA double strand breaks PARP1在DNA双链断裂修复中的多重功能

IF 3 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-07-21 DOI: 10.1016/j.dnarep.2025.103873

Raquel Ortega , Benjamin G. Bitler , Nausica Arnoult

Poly(ADP-ribose) polymerase 1 (PARP1) is one of the most abundant nuclear proteins in human cells and plays critical roles in numerous cellular processes, including the response to DNA damage. PARP1 is activated by and rapidly localizes to both single- and double-strand breaks, where it catalyzes the addition of poly(ADP-ribose) chains onto itself and other chromatin- or repair-associated proteins. While the role of PARP in single-strand break repair is established, its functions at double-strand breaks (DSBs) are more complex, as it can promote or inhibit various steps in the multiple pathways that repair DSBs. In this review, we examine the DSB repair contributions of PARP1, as well as those of PARP2 and PARP3, which are also activated upon damage. We discuss their influence on chromatin regulation at break sites, their role in repair pathway selection, and finally, the regulation of repair mechanisms, including homologous recombination, non-homologous end-joining, and microhomology-mediated end-joining. Understanding these diverse and sometimes opposing roles is especially important in light of the clinical use of PARP inhibitors in cancers deficient in homologous recombination repair.

聚（adp -核糖）聚合酶1 （PARP1）是人类细胞中最丰富的核蛋白之一，在许多细胞过程中起着关键作用，包括对DNA损伤的反应。PARP1被单链和双链断裂激活并迅速定位，在那里它催化多链（adp核糖）链添加到自身和其他染色质或修复相关蛋白上。虽然PARP在单链断裂修复中的作用已经确立，但其在双链断裂（dsb）中的功能更为复杂，因为它可以促进或抑制dsb修复的多种途径中的各个步骤。在这篇综述中，我们研究了PARP1以及PARP2和PARP3对DSB修复的贡献，它们也在损伤时被激活。我们讨论了它们对断裂位点染色质调控的影响，它们在修复途径选择中的作用，以及修复机制的调控，包括同源重组、非同源末端连接和微同源介导的末端连接。鉴于PARP抑制剂在缺乏同源重组修复的癌症中的临床应用，了解这些不同的、有时相反的作用尤为重要。

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引用次数: 0

An economical and rapid method of comet assay and micronucleus cytome assay for genotoxicity biomonitoring using clam, Gafrarium divaricatum (Gmelin, 1791) 一种经济快速的彗星测定和微核细胞组测定法用于蛤蜊遗传毒性生物监测

IF 3 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-07-17 DOI: 10.1016/j.dnarep.2025.103870

M. Harshavarthini , Edward Inpent Campal , Shubra Singh , Nalini Poojary , Martin Xavier , Kiran D. Rasal , Madhuri S. Pathak , Naresh S. Nagpure

The comet assay or single-cell gel electrophoresis and the micronucleus cytome assay have emerged as widely used methods for measuring DNA damage and cytotoxicity in genotoxicity testing and biomonitoring studies. The relative occurrence of micronuclei and other cellular abnormalities in dividing cells is a reliable biomarker of xenobiotic-induced genotoxicity. Bivalves are known for their bioaccumulation capabilities and are ideal bioindicators for monitoring DNA damage and chromosomal mutations. This study focuses on the optimization and standardization of genotoxicity assays, such as comet assay and micronucleus test, using forked venus clam, Gafrarium divaricatum, as a model organism. It highlights the potential of using cost-effective mechanical digestion method to prepare cell suspensions from clam tissues, as opposed to the more expensive enzymatic digestion techniques. It also explored the application of various staining techniques to improve the accuracy of micronucleus scoring, addressing the variability in genotoxicity assays across different laboratories. By developing a species specific standardized protocol for these assays, this investigation aimed to reduce inter-laboratory discrepancies and enhance the reliability of genotoxicity testing in marine organisms, especially in bivalves, thereby facilitating regulatory applications and environmental monitoring.

彗星测定法或单细胞凝胶电泳法和微核细胞组测定法已在遗传毒性测试和生物监测研究中广泛应用于测量DNA损伤和细胞毒性的方法。分裂细胞中微核和其他细胞异常的相对发生是外源生物诱导的遗传毒性的可靠生物标志物。双壳类以其生物积累能力而闻名，是监测DNA损伤和染色体突变的理想生物指标。本研究主要以叉蛤（Gafrarium divaricatum）为模型生物，对彗星试验和微核试验等遗传毒性试验进行优化和标准化。它强调了使用具有成本效益的机械消化方法从蛤蜊组织中制备细胞悬浮液的潜力，而不是更昂贵的酶消化技术。它还探讨了各种染色技术的应用，以提高微核评分的准确性，解决遗传毒性测定在不同实验室的可变性。通过为这些检测制定一种特定物种的标准化方案，本研究旨在减少实验室间的差异，提高海洋生物（特别是双壳类）遗传毒性检测的可靠性，从而促进监管应用和环境监测。

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引用次数: 0

Synthetic cytotoxicity profiling of cohesin mutants highlights recombination-based dependencies 内聚蛋白突变体的合成细胞毒性分析强调了基于重组的依赖性

IF 3 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-07-16 DOI: 10.1016/j.dnarep.2025.103871

Rafaela Horbach Marodin , Ecaterina Cozma , Sivan Reytan-Miron , Nigel J. O’Neil , Peter C. Stirling , Philip Hieter

Cohesin maintains genome integrity through its ability to bind and link DNA molecules via a Structural Maintenance of Chromatin (SMC) activity. These effects are manifested through its major function in sister chromatid cohesion, but also through activities during DNA replication, repair, and transcription. The array of cohesin functions can make interpreting cellular effects of cohesin loss difficult to interpret mechanistically. This is particularly important in cancer where cohesin subunit mutations are common, and where the identification of genetic dependencies would be useful for predicting the response of cohesin-mutated cells to genotoxic challenges. Here we performed a series of synthetic cytotoxicity screens with hypomorphic cohesin alleles in yeast to identify cellular pathways whose loss sensitizes cohesin-mutants to sublethal levels of genotoxic DNA damage. This dataset reveals important roles for cohesin in replication stress and homologous recombination regulation that can leave cohesin mutated cells with a dependency on translesion synthesis for survival.

内聚蛋白通过染色质结构维持（SMC）活性来结合和连接DNA分子，从而维持基因组的完整性。这些作用通过其在姐妹染色单体内聚中的主要功能以及在DNA复制、修复和转录过程中的活动表现出来。内聚蛋白功能的多样性使得内聚蛋白损失对细胞的影响难以从机制上解释。这在癌症中尤其重要，因为黏合蛋白亚基突变是常见的，并且遗传依赖性的鉴定将有助于预测黏合蛋白突变细胞对基因毒性挑战的反应。在这里，我们用酵母中的半形黏合蛋白等位基因进行了一系列的合成细胞毒性筛选，以确定细胞通路，其丢失使黏合蛋白突变体致敏到亚致死水平的基因毒性DNA损伤。该数据集揭示了内聚蛋白在复制胁迫和同源重组调控中的重要作用，这些调控可以使内聚蛋白突变的细胞依赖翻译合成来生存。

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引用次数: 0

From cooperation to conflicts – A complicated relationship between transcription and replication 从合作到冲突——转录与复制之间的复杂关系

IF 3 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-07-16 DOI: 10.1016/j.dnarep.2025.103872

Syed Shahid Musvi , Tatiana N. Moiseeva

A tight coordination between transcription and DNA replication is essential to maintain genome stability. Both excessive transcription and upregulated initiation of DNA replication result in transcription replication conflicts and DNA damage. Interestingly, many replication origins are co-localized with transcription start sites, indicating that transcription may play a role in the initiation of DNA replication. In this review we cover various aspects of replication regulation by transcription - from location of replication origins to various steps of replication initiation, replication timing and transcription-replication conflicts.

转录和DNA复制之间的紧密协调是维持基因组稳定所必需的。过度转录和DNA复制起始上调都会导致转录复制冲突和DNA损伤。有趣的是，许多复制起点与转录起始位点共定位，这表明转录可能在DNA复制的起始中发挥作用。在这篇综述中，我们涵盖了转录调控复制的各个方面-从复制起始的位置到复制起始的各个步骤，复制时间和转录-复制冲突。

引用次数: 0

Transcription-coupled repair of crosslinking DNA damage 交联DNA损伤的转录偶联修复

IF 3 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-07-16 DOI: 10.1016/j.dnarep.2025.103869

Rebecca Roddan, Lucy R. Henderson, Malitha Ratnaweera, Peter J. McHugh

Impediments to faithful transcription must be resolved to ensure accurate gene expression and safeguard normal cellular function. Dedicated DNA repair pathways have therefore evolved to remove transcription-blocking DNA damage, targeted to active genes. Although significant research efforts to date have focussed on the transcription-coupled repair of bulky, UV-induced DNA damage, it is known that other forms of DNA damage can perturb RNA Polymerase II progression. Only in recent years has insight into these pathways emerged, despite the clinical significance of understanding all transcription-coupled repair pathways. These recent observations have highlighted substantial molecular differences in these pathways compared to the canonical UV-damage repair mechanisms. This review summarises our understanding to date of the molecular mechanisms that act to remove both DNA-DNA and DNA-protein crosslinks that block transcription in mammalian cells.

必须解决忠实转录的障碍，以确保准确的基因表达和维护正常的细胞功能。因此，专门的DNA修复途径已经发展到消除转录阻断DNA损伤，针对活性基因。尽管迄今为止重要的研究工作主要集中在转录偶联修复大量紫外线诱导的DNA损伤上，但已知其他形式的DNA损伤可以扰乱RNA聚合酶II的进展。尽管理解所有转录偶联修复途径具有临床意义，但直到最近几年才对这些途径有了深入的了解。这些最近的观察结果强调了这些途径与典型的紫外线损伤修复机制之间的实质性分子差异。这篇综述总结了迄今为止我们对去除哺乳动物细胞中阻断转录的DNA-DNA和dna -蛋白交联的分子机制的理解。

引用次数: 0

The role of human PrimPol active site residue Gln48 in catalysis and complex formation with DNA 人PrimPol活性位点残基Gln48在催化和与DNA形成复合物中的作用

IF 3 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-07-11 DOI: 10.1016/j.dnarep.2025.103867

Elizaveta O. Boldinova , Alena V. Makarova

Human PrimPol is a primase-polymerase involved in the mechanism of DNA synthesis reinitiation at the sites of DNA damage and replication fork collapse. By using its DNA primase activity, PrimPol synthesizes DNA primers which can be utilized by high-fidelity DNA polymerases to resume replication downstream of the damaged site. Disruption of PrimPol function may be associated with an increased risk of cancer and ophthalmologic diseases. Understanding the detailed mechanism of catalysis and regulation of PrimPol activity is crucial for predicting how mutations and polymorphisms affect enzyme function within the cell. In this study, we conducted a biochemical investigation of the role of the conserved Gln48 residue in the PrimPol active site in DNA synthesis by replacing glutamine with a positively charged arginine (Q48R) or a negatively charged glutamic acid (Q48E). The PrimPol variant with the Q48R substitution is also represented in the NCBI dbSNP (rs939272279 A/G). Both substitutions resulted in impaired complex formation of PrimPol with DNA and significantly reduced the catalytic activity of the enzyme, indicating the important role of the Gln48 residue in forming contacts with the template DNA and active site organization. The data obtained suggest that the Q48R substitution may disrupt PrimPol functions.

人PrimPol是一种引物聚合酶，参与DNA损伤和复制叉崩溃位点的DNA合成再起始机制。PrimPol利用其DNA引物酶活性合成DNA引物，这些引物可以被高保真DNA聚合酶利用来恢复受损位点下游的复制。PrimPol功能的破坏可能与癌症和眼科疾病的风险增加有关。了解PrimPol活性的详细催化和调控机制对于预测突变和多态性如何影响细胞内酶的功能至关重要。在这项研究中，我们通过用带正电的精氨酸（Q48R）或带负电的谷氨酸（Q48E）取代谷氨酰胺，对PrimPol活性位点上保守的Gln48残基在DNA合成中的作用进行了生化研究。具有Q48R替换的PrimPol变体也在NCBI dbSNP （rs939272279 A/G）中表示。这两种取代都导致PrimPol与DNA的复合物形成受损，并显著降低了酶的催化活性，这表明Gln48残基在与模板DNA形成接触和活性位点组织方面发挥了重要作用。得到的数据表明，Q48R的取代可能会破坏PrimPol的功能。

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引用次数: 0

Unveiling cGAS mechanisms: Insights into DNA damage and immune sensing in cancer 揭示cGAS机制：对癌症中DNA损伤和免疫感知的见解

IF 3 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-07-09 DOI: 10.1016/j.dnarep.2025.103868

Min-Guk Cho , Gaorav P. Gupta

The innate immune sensing system plays a critical role in recognizing and responding to DNA damage, which is a key factor in cancer development and progression. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, in particular, detects cytosolic double-stranded DNA (dsDNA) and activates the innate immune response. Recent studies have shown that cGAS is sequestered on chromatin by binding to the acidic patch (AP) regions of histones. Upon DNA damage, its ability to bind to chromatin-associated dsDNA fragments requires the DNA damage sensor MRE11. Upon its activation, cGAS triggers an innate immune response that can suppress tumorigenesis. However, the context-specific factors that govern whether cGAS engagement leads to effective STING pathway activation remain incompletely defined, particularly in relation to chromatin context, micronuclear integrity, and post-translational modifications. In this review, we explore the dynamic interplay between DNA damage responses and innate immune signaling through the cGAS-STING axis, with a focus on recent mechanistic advances. We further examine how cancers evade or co-opt this pathway and highlight therapeutic opportunities to exploit cGAS-STING signaling for cancer treatment.

先天免疫感知系统在识别和响应DNA损伤中起着至关重要的作用，这是癌症发生和发展的关键因素。特别是环GMP-AMP合成酶刺激干扰素基因（cGAS-STING）途径，检测胞质双链DNA （dsDNA）并激活先天免疫反应。最近的研究表明，cGAS通过与组蛋白的酸性斑块（AP）区域结合而被隔离在染色质上。在DNA损伤时，其结合染色质相关的dsDNA片段的能力需要DNA损伤传感器MRE11。一旦被激活，cGAS就会触发先天免疫反应，从而抑制肿瘤的发生。然而，控制cGAS参与是否导致STING通路有效激活的环境特异性因素仍然不完全确定，特别是与染色质背景、微核完整性和翻译后修饰有关。在这篇综述中，我们通过cGAS-STING轴探讨了DNA损伤反应和先天免疫信号之间的动态相互作用，并重点介绍了最近的机制进展。我们进一步研究了癌症如何逃避或利用这一途径，并强调了利用cGAS-STING信号进行癌症治疗的治疗机会。

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引用次数: 0

DNA topoisomerase IIß inhibition blocks DNA end resection and synergizes with PARPi in BRCA1-deficient models 在brca1缺陷模型中，DNA拓扑异构酶isß抑制阻断DNA末端切除并与PARPi协同作用

IF 3 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-06-27 DOI: 10.1016/j.dnarep.2025.103866

Rosa Camarillo , Rosario Prados-Carvajal , Andrés Cruz-García , Guillermo Rodríguez-Real , Andrea Herencia-Ropero , Violeta Serra , Sonia Jimeno , Pablo Huertas

DNA end resection is a critical step that governs how a broken chromosome will be repaired. As such, it is heavily regulated by multiple cellular signals and processes. Alterations in the regulation of DNA end resection have consequences for cell survival upon exposure to cytotoxic agents, including those used during cancer chemotherapy. Here, we identified several small molecules that affect the process of DNA end resection. Among them, we focus on determining the mode of action of merbarone, a DNA topoisomerase II inhibitor. We uncover a role of the topoisomerase IIβ isoform in the full processing of DNA breaks. Moreover, we show that the effect of merbarone is affected by the formation of G4 quadruplexes and that BRCA1-deficient cancer cells are sensitive to merbarone. Strikingly, this sensitivity can be partially suppressed in cell lines expressing hypomorphic versions of BRCA1 lacking exon 11, a hypomorph that has been linked to PARPi-resistance. Using cellular models, we show that PARPi- and merbarone-resistant BRCA1 exon 11 mutant cells, but not wildtype BRCA1 cells, are sensitive to the combination of both drugs. Finally, we show that combination of merbarone and the PARPi olaparib has a mild antitumor effect in a PARPi-resistant PDX model bearing a BRCA1 exon 11 mutation.

DNA末端切除是决定断裂染色体如何修复的关键步骤。因此，它受到多种细胞信号和过程的严格调节。DNA末端切除调控的改变对暴露于细胞毒性药物（包括癌症化疗期间使用的药物）后的细胞存活有影响。在这里，我们确定了几个影响DNA末端切除过程的小分子。其中，我们重点研究了DNA拓扑异构酶II抑制剂merbarone的作用模式。我们揭示了拓扑异构酶IIβ异构体在DNA断裂的完整加工中的作用。此外，我们发现merbarone的作用受G4四联体形成的影响，并且brca1缺陷的癌细胞对merbarone敏感。引人注目的是，在表达缺乏外显子11的BRCA1亚型的细胞系中，这种敏感性可以部分抑制，这种亚型与parpi抗性有关。通过细胞模型，我们发现耐PARPi和merbarone的BRCA1外显子11突变细胞，而不是野生型BRCA1细胞，对这两种药物的联合敏感。最后，我们发现merbarone和PARPi olaparib联合使用在携带BRCA1外显子11突变的PARPi耐药PDX模型中具有轻微的抗肿瘤作用。

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引用次数: 0

FBH1 and the replication stress response: Implications for genome stability and cancer development FBH1和复制应激反应：对基因组稳定性和癌症发展的影响

IF 3 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-06-26 DOI: 10.1016/j.dnarep.2025.103865

Joshua L. Turner, Jennifer M. Mason

The replication stress response plays important roles in maintaining genome stability.In this review article, we focus on the role of FBH1 in the replication stress response and promoting death in cells with excessive DNA damage. FBH1-deficiency results in resistance to replication stress. We discuss how loss and gain of FBH1 in a wide variety of cancers can contribute to tumor-associated phenotypes, impact cancer therapies and be exploited for potential targeted therapies.

复制应激反应在维持基因组稳定性中起着重要作用。在这篇综述文章中，我们重点关注FBH1在复制应激反应和促进过度DNA损伤细胞死亡中的作用。fbh1缺乏导致对复制胁迫的抗性。我们讨论了各种癌症中FBH1的缺失和获得如何促进肿瘤相关表型，影响癌症治疗并被用于潜在的靶向治疗。

引用次数: 0

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