IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-12-11 DOI: 10.1016/j.dnarep.2025.103914

Sofie Østergård Bæk , Kristina Keuper , Giacomo Milletti , Alba Adelantado-Rubio , Michael Lisby , Jiri Bartek , Christoffel Dinant , Apolinar Maya-Mendoza

Camptothecin (CPT) and its derivative irinotecan inhibit DNA topoisomerase I (TOP1), inducing replication stress by stabilizing the TOP1 cleavage complex. This prevents DNA re-ligation, resulting in single-stranded breaks that, if unresolved, can cause DNA replication fork collapse and double-stranded breaks. Cells respond to TOP1 inhibitors through homologous recombination (HR) repair and fork protection, with RAD51 playing a central role. However, the full mechanisms of how cells react to TOP1 inhibitors are not fully understood. Here, we systematically investigated cellular responses to TOP1 inhibitors, assessing the effects on DNA damage repair (DDR), replication, and cell viability. Using state-of-the-art quantitative image-based cytometry and single-molecule analyses, we reveal a dose and time-dependent mechanistic switch in DDR pathways, which differentially affects DNA replication. While the replication forks arrest after minutes in the presence of CPT, unexpectedly, after two hours of CPT exposure, the fork speed is faster than in the controls. Furthermore, we explain some of the contrasting effects of the replication fork dynamics and DDR activation triggered by TOP1 inhibition. Finally, we identify cancer genetic vulnerabilities, such as HR deficiency, that may be exploitable with low-dose TOP1 inhibitors.

喜树碱（CPT）及其衍生物伊立替康抑制DNA拓扑异构酶I (TOP1)，通过稳定TOP1切割复合体诱导复制应激。这可以防止DNA重新连接，导致单链断裂，如果不解决，可能导致DNA复制叉崩溃和双链断裂。细胞通过同源重组（homologous recombination， HR）修复和分叉保护对TOP1抑制剂产生应答，RAD51起着核心作用。然而，细胞对TOP1抑制剂反应的完整机制尚不完全清楚。在这里，我们系统地研究了细胞对TOP1抑制剂的反应，评估了对DNA损伤修复（DDR）、复制和细胞活力的影响。利用最先进的定量图像细胞术和单分子分析，我们揭示了DDR通路中剂量和时间依赖的机制开关，这对DNA复制有不同的影响。虽然在CPT存在几分钟后复制分叉停止，但出乎意料的是，在CPT暴露两小时后，分叉速度比对照组快。此外，我们解释了一些由TOP1抑制触发的复制叉动力学和DDR激活的对比效应。最后，我们确定了低剂量TOP1抑制剂可能利用的癌症遗传脆弱性，如HR缺乏。

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引用次数: 0

How DNA secondary structures drive replication fork instability DNA二级结构如何驱动复制叉的不稳定性。

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-12-01 DOI: 10.1016/j.dnarep.2025.103913

Aditya Sethi , María Fernández-Casañas , Billie Delpino , Gideon Coster

DNA secondary structures, such as hairpins, cruciforms, triplexes, G-quadruplexes and iMotifs, are common, dynamic features that replication forks routinely encounter. However, how these structures destabilise the replication fork remains unclear. Here, we propose a framework describing the immediate consequences of replication forks encountering DNA secondary structures. This review considers outcomes according to the affected strand (leading or lagging) and the timing of structure formation, linking strand geometry and folding dynamics to replisome behaviour. Stable, pre-formed structures on the leading strand template either impede, or are bypassed by, the CMG (CDC45-MCM-GINS) helicase, frequently leaving single-stranded DNA (ssDNA) gaps. Leading strand structures inhibit DNA polymerase ε (Pol ε), induce fork uncoupling, again producing post-replicative ssDNA gaps which can channel into fork reversal or PrimPol-dependent repriming. Lagging strand template structures inhibit DNA polymerase δ (Pol δ) and structures on 5′ flaps impair Okazaki fragment maturation (OFM); both impediments yield ssDNA nicks or gaps. In each case, replication protein A (RPA) availability and the replication checkpoint define a tolerance window and coordinate hand-offs to accessory helicases, Pol δ strand displacement synthesis, and translesion synthesis (TLS). Immediate double-strand breaks (DSBs) are unlikely as an immediate consequence. Instead, we propose strand-specific ssDNA gaps predominate and may later be converted into DSBs during late S/G2 processing, mitosis, or the next S phase. This review integrates mechanisms to connect structure dynamics with fork responses and downstream ssDNA gaps and breaks, providing possible models of structure-induced genome instability.

DNA二级结构，如发夹、十字形、三联体、g -四联体和i基序，是复制叉经常遇到的常见的动态特征。然而，这些结构如何破坏复制叉的稳定性仍不清楚。在这里，我们提出了一个框架来描述复制叉遇到DNA二级结构的直接后果。本综述根据受影响的链（前导或滞后）和结构形成的时间考虑结果，将链的几何形状和折叠动力学与复制体行为联系起来。前导链模板上稳定的预形成结构阻碍或绕过CMG （CDC45-MCM-GINS）解旋酶，经常留下单链DNA （ssDNA）间隙。前导链结构抑制DNA聚合酶ε (Pol ε)，诱导分叉解耦，再次产生复制后的ssDNA间隙，该间隙可以引导分叉逆转或primpol依赖的重新启动。后链模板结构抑制DNA聚合酶δ (Pol δ), 5'瓣结构抑制Okazaki片段成熟（OFM）；这两种障碍都会产生ssDNA缺口。在每种情况下，复制蛋白A （RPA）的可用性和复制检查点定义了一个耐受窗口，并协调与辅助解旋酶、Pol δ链位移合成和翻译合成（TLS）的交接。立即双链断裂（DSBs）不太可能作为直接后果。相反，我们认为链特异性的ssDNA缺口占主导地位，并可能在S/G2加工后期、有丝分裂或下一个S期转化为dsb。本文综述了将结构动力学与叉反应和下游ssDNA间隙和断裂联系起来的机制，为结构诱导的基因组不稳定提供了可能的模型。

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引用次数: 0

Recent advances in understanding the molecular mechanisms of SLX4 recruitment in the replication stress response SLX4在复制应激反应中募集的分子机制研究进展

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-12-01 DOI: 10.1016/j.dnarep.2025.103911

Takuma Okano , Minoru Takata , Masatoshi Fujita , Yoko Katsuki

Although DNA replication is tightly regulated, various impediments can stall DNA replication forks. SLX4 is a scaffold protein that responds to different types of replication stress. While the yeast Slx4 interacts mainly with structure-specific endonucleases, mammalian SLX4 collaborates with not only such nucleases but also a telomere-binding factor, a DNA helicase, and DNA repair proteins to resolve a variety of DNA intermediates arising from replication stress, thereby maintaining genome stability. Since SLX4 was identified as a causative gene for Fanconi anemia in humans, with UBZ4 domain–deleting mutation observed in a few patients, the UBZ4 domains have been highlighted as a key determinant for its recruitment to stalled forks, which has attracted considerable attention. While several studies have advanced our understanding of how SLX4 is recruited under distinct replication stresses, the precise details and context-specific regulation remain incompletely understood. In this review, we summarize what is currently known about SLX4, including its interactions with partner proteins and its roles under different types of replication stress. We also discuss the molecular basis of its recruitment to stalled forks, with particular emphasis on recent advances in understanding the contributions of the ubiquitin-binding zinc finger type 4 (UBZ4) domains and the SUMO-interacting motif (SIM) in the DNA replication stress response.

尽管DNA复制受到严格调控，但各种障碍可以阻止DNA复制分叉。SLX4是一种对不同类型的复制应激作出反应的支架蛋白。酵母Slx4主要与结构特异性核酸内切酶相互作用，哺乳动物Slx4不仅与这些核酸酶相互作用，还与端粒结合因子、DNA解旋酶和DNA修复蛋白协同作用，以解决复制应激产生的各种DNA中间体，从而维持基因组的稳定性。由于SLX4被确定为人类范可尼贫血的致病基因，在少数患者中观察到UBZ4结构域删除突变，UBZ4结构域被强调为其招募到停滞分叉的关键决定因素，这引起了相当大的关注。虽然有几项研究提高了我们对SLX4如何在不同的复制压力下被招募的理解，但精确的细节和上下文特定的调控仍然不完全清楚。在本文中，我们对目前已知的SLX4进行了综述，包括其与伴侣蛋白的相互作用及其在不同类型复制胁迫下的作用。我们还讨论了其招募到停滞分叉的分子基础，特别强调了在理解泛素结合锌指型4 （UBZ4）结构域和sumo相互作用基元（SIM）在DNA复制应激反应中的贡献方面的最新进展。

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引用次数: 0

Fueling for the finish line: Control of human telomerase activity by nucleotide metabolism 为终点线加油：通过核苷酸代谢控制人类端粒酶活性。

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-12-01 DOI: 10.1016/j.dnarep.2025.103912

William Mannherz , Suneet Agarwal

Telomeres are repetitive DNA sequences that preserve genome integrity. Human telomere length is kept in a tight window through a balance between telomere erosion during genome replication and telomere elongation by the telomerase reverse transcriptase. In humans, genetically determined telomere length is associated with lifespan, while inherited defects in telomere length maintenance genes predispose to a spectrum of lethal diseases termed telomere biology disorders (TBDs). Recently, dNTP metabolism has emerged as a previously underappreciated pathway that is critical for human telomerase regulation and telomere length control. Genome-wide association studies have implicated variation in several dNTP metabolism genes with human telomere length. Genetic variants at the TYMS locus, which encodes the rate limiting thymidine synthesis enzyme thymidylate synthase, have been shown to cause the TBD dyskeratosis congenita. Genome-wide CRISPR/Cas9 functional screening has linked telomere length control to multiple key dNTP metabolism genes. Remarkably, mechanistic studies emerging from these genetic data have revealed a profound, bidirectional sensitivity of human telomerase activity to cellular dNTP levels, that is readily manipulated through several metabolic control nodes. Here, we review the emerging genetic evidence and mechanistic studies supporting the relationship between dNTP metabolism and telomere length control. We present an integrated model for human telomerase regulation, wherein the levels of dNTP substrates govern telomerase reverse transcriptase activity and in turn human telomere length. We discuss the therapeutic prospects and recent trials for manipulating dNTP metabolism to treat TBDs and related degenerative diseases.

端粒是保持基因组完整性的重复DNA序列。人类端粒长度保持在一个紧密的窗口通过端粒侵蚀之间的平衡基因组复制和端粒延长端粒逆转录酶。在人类中，遗传决定的端粒长度与寿命有关，而端粒长度维持基因的遗传缺陷易导致一系列被称为端粒生物学障碍（tbd）的致命疾病。最近，dNTP代谢已成为一种以前未被重视的途径，对人类端粒酶调节和端粒长度控制至关重要。全基因组关联研究表明，几种dNTP代谢基因的变异与人类端粒长度有关。编码限速胸苷合成酶胸苷酸合成酶的TYMS位点的遗传变异已被证明可导致TBD先天性角化不良。全基因组CRISPR/Cas9功能筛选将端粒长度控制与多个关键的dNTP代谢基因联系起来。值得注意的是，从这些遗传数据中出现的机制研究揭示了人类端粒酶活性对细胞dNTP水平的深刻的双向敏感性，这很容易通过几个代谢控制节点来操纵。在这里，我们回顾了支持dNTP代谢与端粒长度控制之间关系的新出现的遗传证据和机制研究。我们提出了一个人类端粒酶调节的综合模型，其中dNTP底物的水平控制端粒酶逆转录酶活性，进而控制人类端粒长度。我们讨论了操纵dNTP代谢治疗tbd和相关退行性疾病的治疗前景和最近的试验。

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引用次数: 0

DNA G-quadruplexes: Structural and functional insights DNA g -四联体：结构和功能的见解

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-11-11 DOI: 10.1016/j.dnarep.2025.103910

Sagun Jonchhe, Sudipta Lahiri, Eli Rothenberg

Guanine-rich regions in the human genome have the intrinsic ability to fold into G-quadruplex (G4) secondary structures, stabilized by stacked guanine quartets. There is considerable biochemical and structural evidence demonstrating formation of G4 structures in vitro under biomimetic conditions. Recently, emerging studies have also provided compelling data that authenticates the existence of these DNA G4 structures in vivo. These G4 structures, present in both DNA and RNA, are involved in key biological processes such as transcription, replication and the maintenance of genomic integrity. They have also been linked to different diseases. Given their association with multiple proteins across the DNA repair machinery, G4 structures are particularly prominent in various cancers and have been recognized as promising targets for therapeutic research. In this review, we first highlight the identification, structure and conformations of DNA G4s. We then discuss the influence of biomimetic microenvironment on G4 formation and its implication for genome function and maintenance. Next, we elaborate on the genome-wide occurrence of G4s and their roles in transcription, replication, and DNA repair. Furthermore, we explore drug design strategies aimed at selectively targeting the G4 structures and emphasize the potential of DNA G4s in cancer therapy, particularly in the context of synthetic lethality. Finally, we discuss recent advances and emerging roles of G4 biology that potentially explore new avenues of research. Taken together, this review aims to provide a comprehensive overview of DNA G4 structure and function, accentuate its role in genome maintenance and underscore their significance in cancer research.

人类基因组中富含鸟嘌呤的区域具有固有的折叠成g -四重体（G4）二级结构的能力，通过堆叠的鸟嘌呤四重体来稳定。有大量的生化和结构证据表明，在体外仿生条件下，G4结构的形成。最近，新兴的研究也提供了令人信服的数据，证明这些DNA G4结构在体内的存在。这些G4结构存在于DNA和RNA中，参与关键的生物过程，如转录、复制和基因组完整性的维持。它们还与不同的疾病有关。考虑到G4结构与DNA修复机制中的多种蛋白质的关联，G4结构在各种癌症中尤为突出，并已被认为是治疗研究的有希望的靶点。在这篇综述中，我们首先介绍了DNA G4s的鉴定、结构和构象。然后讨论了仿生微环境对G4形成的影响及其对基因组功能和维持的启示。接下来，我们详细阐述了G4s的全基因组发生及其在转录、复制和DNA修复中的作用。此外，我们探索了选择性靶向G4结构的药物设计策略，并强调了DNA G4在癌症治疗中的潜力，特别是在合成致死性的背景下。最后，我们讨论了G4生物学的最新进展和新兴角色，这些研究可能会探索新的研究途径。综上所述，本文旨在全面概述DNA G4的结构和功能，强调其在基因组维持中的作用，并强调其在癌症研究中的意义。

{"title":"DNA G-quadruplexes: Structural and functional insights","authors":"Sagun Jonchhe, Sudipta Lahiri, Eli Rothenberg","doi":"10.1016/j.dnarep.2025.103910","DOIUrl":"10.1016/j.dnarep.2025.103910","url":null,"abstract":"<div><div>Guanine-rich regions in the human genome have the intrinsic ability to fold into G-quadruplex (G4) secondary structures, stabilized by stacked guanine quartets. There is considerable biochemical and structural evidence demonstrating formation of G4 structures <em>in vitro</em> under biomimetic conditions. Recently, emerging studies have also provided compelling data that authenticates the existence of these DNA G4 structures <em>in vivo</em>. These G4 structures, present in both DNA and RNA, are involved in key biological processes such as transcription, replication and the maintenance of genomic integrity. They have also been linked to different diseases. Given their association with multiple proteins across the DNA repair machinery, G4 structures are particularly prominent in various cancers and have been recognized as promising targets for therapeutic research. In this review, we first highlight the identification, structure and conformations of DNA G4s. We then discuss the influence of biomimetic microenvironment on G4 formation and its implication for genome function and maintenance. Next, we elaborate on the genome-wide occurrence of G4s and their roles in transcription, replication, and DNA repair. Furthermore, we explore drug design strategies aimed at selectively targeting the G4 structures and emphasize the potential of DNA G4s in cancer therapy, particularly in the context of synthetic lethality. Finally, we discuss recent advances and emerging roles of G4 biology that potentially explore new avenues of research. Taken together, this review aims to provide a comprehensive overview of DNA G4 structure and function, accentuate its role in genome maintenance and underscore their significance in cancer research.</div></div>","PeriodicalId":300,"journal":{"name":"DNA Repair","volume":"156 ","pages":"Article 103910"},"PeriodicalIF":2.7,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145519104","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}

引用次数: 0

Overcoming natural replication barriers formed by DNA structures and the role of repositioning to the nuclear periphery 克服由DNA结构形成的自然复制障碍和重新定位到核外围的作用

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-11-01 DOI: 10.1016/j.dnarep.2025.103903

Jan Leendert Boer , Tyler M. Maclay , Nolan T. Caile, Catherine H. Freudenreich

Endogenous barriers to DNA replication, such as repetitive DNA, non-B DNA structures, and protein barriers present significant challenges to replication. Upon encountering one of these barriers, cells employ a number of strategies to ensure completion of replication. Some of these pathways operate at the stalled replication fork and others occur post-replicatively. These pathways vary both in their timing and the nuclear location in which they occur. Here we review how cells deal with endogenous sources of replication stress, with a focus on structure-forming DNA repeats, and our current understanding of how cells use nuclear positioning to facilitate the repair of natural replication barriers.

DNA复制的内源性障碍，如重复DNA、非b DNA结构和蛋白质障碍，对复制提出了重大挑战。在遇到这些障碍时，细胞采用多种策略来确保完成复制。其中一些途径在停滞的复制分叉处起作用，另一些则发生在复制后。这些途径在其发生的时间和核位置上各不相同。在这里，我们回顾了细胞如何处理内源性复制应激源，重点是结构形成的DNA重复，以及我们目前对细胞如何利用核定位来促进自然复制屏障的修复的理解。

引用次数: 0

MCM8/9 and FANCD2 interact within a shared pathway in response to replication stress caused by DNA crosslinks MCM8/9和FANCD2在一个共享的途径中相互作用，以响应DNA交联引起的复制应激

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-11-01 DOI: 10.1016/j.dnarep.2025.103909

Rashini Y. Beragama Arachchi , Desmond C. Okafor, Andrew J. Snyder, Michael A. Trakselis

The Fanconi anemia (FA) protein FANCD2, and MCM8/9 heterohexameric helicase complex are critical for maintaining genomic integrity in response to replication stress, however, the nature of their relationship remains unclear. Here, we show that MCM8/9 interacts and functionally cooperates with FANCD2 within a complex during the repair of DNA interstrand crosslinks (ICLs). Using immunofluorescence and co-immunoprecipitation studies, we show that MCM8/9 interacts with the FANCD2 complex through its core domain. FANCD2 is essential for the recruitment of MCM8/9 to ICL damage induced nuclear foci but acts independently of FANCD2 monoubiquitination. Although MCM8/9 foci formation requires its intact ATPase activity, the BRCv motif within the MCM9 C-terminal extension (CTE) and the accessory protein, HROB, these are not required for FANCD2 binding, highlighting a distinction between physical interaction and functional activation. Interestingly, FANCD2 foci formation increases in MCM8 or MCM9 knockout cells or with knockdown of the activator, HROB, suggesting that MCM8/9 functions to mitigate replication-associated stress. γH2AX DNA damage assays and cell survival assays show that combined loss of MCM9 and FANCD2 do not cause additive DNA damage beyond individual knockouts, indicating an epistatic relationship of MCM8/9 with FANCD2, functioning in the same DNA repair pathway. Together, our findings identify MCM8/9 as a downstream interactor and effector of FANCD2/I critical for resolving ICL induced DNA damage.

范可尼贫血（FA）蛋白FANCD2和MCM8/9异六聚解旋酶复合物在应对复制应激时维持基因组完整性至关重要，然而，它们之间关系的本质尚不清楚。在这里，我们发现MCM8/9在DNA链间交联（ICLs）修复过程中与复合物内的FANCD2相互作用并在功能上合作。通过免疫荧光和共免疫沉淀研究，我们发现MCM8/9通过其核心结构域与FANCD2复合物相互作用。FANCD2对于MCM8/9募集到ICL损伤诱导的核病灶至关重要，但独立于FANCD2单泛素化。虽然MCM8/9病灶形成需要其完整的atp酶活性、MCM9 c端延伸（CTE）内的BRCv基序和辅助蛋白HROB，但这些都不是FANCD2结合所必需的，这突出了物理相互作用和功能激活之间的区别。有趣的是，在MCM8或MCM9敲除细胞中，FANCD2灶形成增加，或者激活因子HROB被敲除，这表明MCM8/9具有减轻复制相关应激的功能。γ - h2ax DNA损伤实验和细胞存活实验显示，MCM9和FANCD2的联合缺失并不会导致除单个敲除外的附加DNA损伤，这表明MCM8/9与FANCD2存在显性关系，它们在相同的DNA修复途径中起作用。总之，我们的研究结果确定MCM8/9是FANCD2/I的下游相互作用因子和效应因子，对解决ICL诱导的DNA损伤至关重要。

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引用次数: 0

Base excision repair in chromatin: A tug-of-war for DNA damage 染色质中的碱基切除修复：DNA损伤的拔河。

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-11-01 DOI: 10.1016/j.dnarep.2025.103908

Abigayle F. Vito , Daniel J. Boesch , Ava M. Hammons , Bret D. Freudenthal , Tyler M. Weaver

Base excision repair (BER) is a genome surveillance pathway responsible for repairing DNA base lesions distributed throughout the chromatinized eukaryotic genome. However, chromatin structure acts as a dynamic structural barrier that restricts access to DNA and must be overcome for BER to proceed efficiently. In this perspective, we summarize recent advances that have shaped our understanding of BER in chromatin, with a focus on the structural mechanisms employed by core BER enzymes to recognize and repair DNA lesions within the nucleosome. We highlight how DNA accessibility dictates BER enzyme activity and discuss the concepts of localized and global DNA sculpting as emerging strategies for lesion recognition and repair. We propose that BER within the nucleosome represents a molecular “tug-of-war”, where the histone octamer and the BER enzymes are in a constant competition for access to the damaged nucleosomal DNA. The outcome of this competition is dictated by the position of the DNA lesion within the nucleosome, which ultimately defines the efficiency of BER enzymes within chromatin. We also explore possible mechanisms used by ATP-dependent chromatin remodeling to facilitate BER within the nucleosome. Together, these recent advances provide a framework for understanding BER in chromatin and outline key unanswered questions regarding chromatin-based BER.

碱基切除修复（BER）是一种基因组监测途径，负责修复分布在染色质化真核生物基因组中的DNA碱基损伤。然而，染色质结构作为一个动态的结构屏障，限制了DNA的进入，必须克服它才能有效地进行BER。从这个角度来看，我们总结了最近的进展，这些进展已经形成了我们对染色质中BER的理解，重点是核心BER酶识别和修复核小体内DNA损伤的结构机制。我们强调了DNA可及性如何决定了BER酶的活性，并讨论了局部和全局DNA雕刻作为损伤识别和修复的新兴策略的概念。我们认为核小体内的BER代表了一种分子“拔河”，组蛋白八聚体和BER酶为了进入受损的核小体DNA而不断竞争。这种竞争的结果取决于核小体内DNA损伤的位置，这最终决定了染色质内BER酶的效率。我们还探索了atp依赖性染色质重塑促进核小体内BER的可能机制。总之，这些最新进展为理解染色质中的BER提供了一个框架，并概述了关于基于染色质的BER的关键未解问题。

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引用次数: 0

Lets talk about ataxia-telangiectasia: Meeting report of the AT clinical research conference June 2025 让我们谈谈共济失调-毛细血管扩张：2025年6月AT临床研究会议会议报告。

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-11-01 DOI: 10.1016/j.dnarep.2025.103907

David Coman , Penny Jeggo , Martin Lavin

Almost fifty years after the identification of ataxia telangiectasia (A-T) as a radiosensitive disorder and thirty years following the identification of ataxia telangiectasia mutated (ATM) as the defective gene, clinicians and scientists gathered at Loughborough University, UK from June 25th -27th 2025 for an Ataxia Telangiectasia Clinical Research Conference. The mix of expertise of clinicians and scientists with basic and translational expertise ensured that a focus was on how to exploit our knowledge of ATM’s function to clinical benefit. Considerable emphasis was placed on the role of ATM in the DNA damage response and the consequences in this multisystem disease, including the neurodegenerative phenotype. The increasingly recognized role of ATM in oxidative stress was also considered and how it was pertinent to mitochondrial dysfunction, metabolic abnormalities and energy metabolism in A-T. The implications of these roles of ATM in protecting the genome/cell and the development of new technology, such as organoids, were widely discussed in the clinical setting of patients with A-T. An important contribution to the meeting was the description of pathways /mechanisms that have led to the development of therapeutic approaches for A-T including the use of specific antisense oligonucleotides to restore ATM function in patients; delivery of full-length ATM cDNA to A-T cells; eDSP (formerly EryDex) that encapsulates dexamethasone sodium phosphate in a patient’s own red blood cells and the use of small molecules (triheptanoin, nicotinamide riboside and N-acetyl leucine) to correct mitochondrial and metabolic function.

在确定共济失调毛细血管扩张症（a - t）为放射敏感疾病近50年后，在确定共济失调毛细血管扩张突变（ATM）为缺陷基因30年后，临床医生和科学家于2025年6月25日至27日聚集在英国拉夫堡大学，参加共济失调毛细血管扩张症临床研究会议。临床医生和科学家的专业知识与基础和转化专业知识的结合确保了重点是如何利用我们对ATM功能的了解来实现临床效益。相当多的重点放在了ATM在DNA损伤反应中的作用和这种多系统疾病的后果，包括神经退行性表型。我们还考虑了ATM在氧化应激中的作用，以及它如何与线粒体功能障碍、代谢异常和A-T中的能量代谢相关。在A-T患者的临床环境中，人们广泛讨论了ATM在保护基因组/细胞和新技术（如类器官）发展中的作用。会议的一个重要贡献是描述了导致A-T治疗方法发展的途径/机制，包括使用特定的反义寡核苷酸来恢复患者的ATM功能；全长ATM cDNA传递到A-T细胞；eDSP（以前的EryDex）将地塞米松磷酸钠封装在患者自身的红细胞中，并使用小分子（三庚烷酸、烟酰胺核苷和n -乙酰亮氨酸）来纠正线粒体和代谢功能。

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引用次数: 0

DNA damage response and its clinical implications in pediatric cancers DNA损伤反应及其在儿童癌症中的临床意义

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-10-18 DOI: 10.1016/j.dnarep.2025.103906

Yiyan Zhang , Jiyuan Teng , Xiaolong Chen , Bin-Bing S. Zhou

DNA damage response (DDR) is a complex network of biological pathways, maintaining eukaryotic genetic stability and frequently altered in cancer cells. Aberrant DDR regulation could be a double-edge sword in cancer: DDR defects could lead to genetic instability driving the acquisition of cancer mutations, while alternative DDR pathways could provide the survival benefits for genetic-unstable cancer cells. Targeting DDR defects in cancer, most noticeably through PARP inhibitors, exhibit impressive clinical efficacy in multiple cancer types. Here, we update recent progress concerning DDR and its inhibitors in pediatric cancers, from molecular mechanism to clinical practice.

DNA损伤反应（DDR）是一个复杂的生物通路网络，维持真核生物的遗传稳定性，在癌细胞中经常发生改变。在癌症中，异常的DDR调控可能是一把双刃剑：DDR缺陷可能导致遗传不稳定驱动癌症突变的获得，而替代的DDR途径可能为遗传不稳定的癌细胞提供生存益处。针对癌症中的DDR缺陷，最明显的是通过PARP抑制剂，在多种癌症类型中表现出令人印象深刻的临床疗效。在这里，我们更新了DDR及其抑制剂在儿童癌症中的最新进展，从分子机制到临床实践。

引用次数: 0

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