DNA Repair最新文献

英文中文

An antimorphic mutant of Brh2 resulting from a conservative amino acid change within the BRC element Brh2的一种反胚突变体，由BRC元件中保守的氨基酸变化引起。

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2026-05-01 Epub Date: 2026-04-30 DOI: 10.1016/j.dnarep.2026.103936

Jeanette H. Sutherland , Gary E. Xavier Valdez , William K. Holloman

Brh2, the streamlined BRCA2 family protein from Ustilago maydis, directs homologous recombination by modulating Rad51 filament dynamics through a single BRC element. Here, we describe an unusual antimorphic mutation within the BRC β-hairpin of Brh2, in which the pivotal phenylalanine residue in the sequence mimicking the Rad51 polymerization motif is replaced by methionine. This methionine-for-phenylalanine substitution in the BRC of Brh2 results in a DNA repair defect more severe than the null allele, while the cognate methionine-for-phenylalanine substitution in Rad51’s polymerization motif supports normal function. The dichotomy suggests that the switch to methionine from phenylalanine exerts distinct structural effects depending on molecular context. Suppression of the antimorphic phenotype by a secondary mutation (T296A) destabilizing the β-hairpin implies that the deleterious activity of the mutant variant requires an intact BRC fold. Relocation of the mutant BRC to an ectopic site within Brh2 mitigates the defect. This indicates there is positional dependence and hierarchical use of BRC modules within the protein. Biochemical assays with BRC polypeptides demonstrate that the BRC^F294M variant is reduced in ability to form stable complexes with free Rad51. However, analysis shows BRC^F294M engages Rad51–ssDNA filaments aberrantly promoting atypical aggregation rather than normal filament dynamics. These findings suggest a mechanistic basis for this antimorphic BRC mutation and highlight the critical influence of BRC structural context in governing Rad51 filament dynamics and DNA repair proficiency.

Brh2是来自黑穗病菌的流线型BRCA2家族蛋白，通过单个BRC元件调节Rad51丝动力学来指导同源重组。在这里，我们描述了Brh2的BRC β-发夹中的一个不寻常的反形态突变，其中模仿Rad51聚合基序的序列中的关键苯丙氨酸残基被蛋氨酸取代。Brh2的BRC中的甲硫氨酸对苯丙氨酸的替代导致比空等位基因更严重的DNA修复缺陷，而Rad51聚合基序中的同源甲硫氨酸对苯丙氨酸的替代支持正常功能。这种二分法表明，从苯丙氨酸到蛋氨酸的转换根据分子环境具有不同的结构效应。次级突变（T296A）破坏β-发夹的稳定，从而抑制反形态表型，这意味着突变变体的有害活性需要完整的BRC折叠。将突变体BRC重新定位到Brh2内的异位位点可以减轻这种缺陷。这表明在蛋白质中存在位置依赖性和BRC模块的分层使用。用BRC多肽进行的生化分析表明，BRCF294M变体与游离Rad51形成稳定复合物的能力降低。然而，分析显示BRCF294M与Rad51-ssDNA丝结合异常促进非典型聚集，而不是正常的丝动力学。这些发现提示了这种反同形BRC突变的机制基础，并强调了BRC结构背景在控制Rad51丝动力学和DNA修复能力方面的关键影响。

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引用次数: 0

Richard Gatti: From concert pianist to bone marrow transplants and the DNA damage response syndrome, ataxia-telangiectasia 理查德·加蒂：从音乐会钢琴家到骨髓移植和DNA损伤反应综合征，共济失调毛细血管扩张。

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2026-03-01 Epub Date: 2026-02-26 DOI: 10.1016/j.dnarep.2026.103929

Martin Lavin , A.M.R. Taylor , Yosef Shiloh

引用次数: 0

Sgs1 and Esc2 suppress chromosome translocations induced by a replication fork barrier in Saccharomyces cerevisiae Sgs1和Esc2抑制酿酒酵母复制叉屏障诱导的染色体易位。

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2026-03-01 Epub Date: 2026-03-11 DOI: 10.1016/j.dnarep.2026.103930

Léa Marie , Marina K. Triplett , Iffat Ahmed , Lorraine S. Symington

Replication stress is recognized as a major cause of genomic instability in eukaryotes and is associated with various human pathologies, including cancer. To investigate the mechanisms driving gross chromosomal rearrangements in response to replication stress, we used the bacterial Tus/Ter barrier to engineer a site-specific replication fork block in the Saccharomyces cerevisiae genome. Surprisingly, we find that replication fork stalling adjacent to a region sharing homology with other chromosomes only modestly induces translocations in wild-type cells. However, the frequency of chromosome translocations is greatly increased in the absence of Sgs1 or Esc2. We show that the elevated frequency of Tus/Ter-induced translocations in sgs1Δ and esc2Δ mutants is completely dependent on RAD51, consistent with their formation by homologous recombination. In addition, we find that Exo1 nuclease contributes to the high frequency of chromosome translocations observed in sgs1Δ and esc2Δ cells, while the Mph1 translocase participates in replication stress-induced GCRs mostly in the absence of Esc2. Based on our findings, we propose that different factors contribute positively or negatively to the formation of chromosomal rearrangements associated with replication stress.

复制应激被认为是真核生物基因组不稳定的主要原因，并与包括癌症在内的各种人类病理有关。为了研究在复制胁迫下驱动总体染色体重排的机制，我们利用细菌Tus/Ter屏障在酿酒酵母基因组中设计了一个位点特异性复制叉块。令人惊讶的是，我们发现，在野生型细胞中，与其他染色体共享同源的区域相邻的复制叉只会适度地诱导易位。然而，在缺少Sgs1或Esc2的情况下，染色体易位的频率大大增加。我们发现，在sgs1Δ和esc2Δ突变体中，Tus/ ter诱导易位的频率升高完全依赖于RAD51，这与它们的同源重组形成一致。此外，我们发现Exo1核酸酶有助于sgs1Δ和esc2Δ细胞中观察到的染色体易位的高频率，而Mph1易位酶主要在没有Esc2的情况下参与复制应激诱导的gcr。根据我们的研究结果，我们提出不同的因素对与复制应激相关的染色体重排的形成有积极或消极的影响。

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引用次数: 0

B cell receptor stimulation inhibits class switch recombination through elevated DNA repair B细胞受体刺激通过提高DNA修复抑制类开关重组

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2026-03-01 Epub Date: 2026-03-08 DOI: 10.1016/j.dnarep.2026.103931

Robert W. Maul , Rhonda L. McFleder , Zheng Cao , Darrell D. Norton , Jana Ridani , Philip Barbulescu , Alberto Martin , Javier M. Di Noia , Patricia J. Gearhart

Antibody diversity in B cells arises from the activity of activation-induced deaminase (AID), which introduces uracils into DNA of the immunoglobulin loci. The presence of uracil initiates a cascade of mutagenic events, resulting in somatic hypermutation and class switch recombination (CSR). To produce CSR, uracils are removed from DNA by uracil DNA glycosylase (UNG), resulting in formation of an abasic site, which is subsequently transformed into a double-stand break and promotes recombination to another constant gene. While the classical model indicates that B cells are activated when the IgM receptor binds antigen, stimulation of cells ex vivo with anti-IgM is insufficient for CSR. In fact, anti-IgM stimulation has a strong inhibitory effect on CSR when added together with lipopolysaccharide (LPS). To determine the mechanism of anti-IgM inhibition of CSR, we examined the known components required for CSR: AID and UNG. After stimulation with anti-IgM and LPS, AID was expressed and recruited to the immunoglobulin loci, and UNG levels increased and prevented uracil accumulation. We also linked the increased expression of UNG to the cell-cycle, as the presence of anti-IgM allowed cells to enter S-phase sooner. Therefore, for efficient CSR, AID-induced uracils must accumulate to sufficient levels before initiating S-phase, to provide more substrate for UNG and endonuclease to generate mutagenic strand breaks. If cell division occurs too early, as in the case of stimulation with anti-IgM and LPS, UNG is quickly upregulated and removes the uracils before they can accumulate, resulting in faithful DNA repair and less CSR.

B细胞中的抗体多样性源于激活诱导脱氨酶（AID）的活性，它将尿嘧啶引入免疫球蛋白位点的DNA中。尿嘧啶的存在引发一系列诱变事件，导致体细胞超突变和类开关重组（CSR）。为了产生CSR，尿嘧啶通过尿嘧啶DNA糖基化酶（UNG）从DNA中去除，导致形成一个基本位点，随后转化为双支架断裂，并促进重组为另一个恒定基因。虽然经典模型表明，当IgM受体结合抗原时，B细胞被激活，但体外用抗IgM刺激细胞不足以引起CSR。事实上，当与脂多糖（LPS）一起添加抗igm刺激时，对CSR具有较强的抑制作用。为了确定抗igm抑制CSR的机制，我们检查了CSR所需的已知成分：AID和UNG。在抗igm和LPS刺激后，AID被表达并募集到免疫球蛋白位点，UNG水平升高并阻止尿嘧啶积聚。我们还将UNG的表达增加与细胞周期联系起来，因为抗igm的存在使细胞更快地进入s期。因此，为了实现有效的CSR，艾滋病诱导的尿嘧啶必须在启动s期之前积累到足够的水平，以便为UNG和内切酶提供更多的底物来产生诱变链断裂。如果细胞分裂发生得太早，如在抗igm和LPS刺激的情况下，UNG会迅速上调，并在尿嘧啶积聚之前将其清除，从而导致DNA的可靠修复和较少的CSR。

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引用次数: 0

Evidence that MutSβ repairs indels generated by mispair initiated template slippage MutSβ修复由错配产生的缺陷的证据引发了模板滑移。

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2026-03-01 Epub Date: 2026-03-12 DOI: 10.1016/j.dnarep.2026.103932

Scott A. Lujan, Alan B. Clark, Jessica S. Williams, Thomas A. Kunkel

This study examines the specificity of MutSβ dependent DNA mismatch repair (MMR) at the URA3 reporter gene in Saccharomyces cerevisiae. Addition and deletion mutations containing multiple base changes are observed at elevated rates in msh3∆ strains. This is consistent with a role for MutSβ in repairing multibase mismatches, such as those important in development of certain diseases and possibly including those made during Okazaki fragment maturation. Mutations containing single C-G base pair deletions are also observed at elevated rates in msh3∆ strains. These mutations are observed at still higher rates in msh3∆ strains with mutator variants of the three major replicases, implicating a defect in insertion/deletion repair during nuclear DNA replication. These deletions are observed at only a subset of detectable locations in URA3 and they occur at higher rates in one of two orientations of URA3 relative to the nearest replication origin. This subset of sites has a strong local DNA sequence context bias suggesting that the deletions are initiated by transient base•base mismatches which lead to template strand slippage, a type of transient initiator mutagenesis (TIM). We conclude that these mispair-initiated template slippage events require MMR via MutSβ before the next round of DNA synthesis to prevent deletion of an unpaired cytosine in the template strand.

本研究检测了酿酒酵母URA3报告基因上MutSβ依赖性DNA错配修复（MMR）的特异性。在msh3∆菌株中观察到含有多个碱基变化的添加和删除突变的速率升高。这与MutSβ在修复多碱基错配中的作用是一致的，这些错配在某些疾病的发展中很重要，可能包括在冈崎片段成熟过程中产生的错配。在msh3∆菌株中也观察到含有单个C-G碱基对缺失的突变率升高。这些突变在具有三种主要复制酶突变变体的msh3∆菌株中观察到的发生率更高，这表明在核DNA复制过程中插入/删除修复存在缺陷。这些缺失仅在URA3中可检测位置的一个子集中观察到，并且相对于最近的复制起点，它们在URA3的两个方向中的一个方向上发生的比率更高。这部分位点具有强烈的局部DNA序列背景偏差，这表明这些缺失是由碱基与碱基不匹配引起的模板链滑移引起的，这是一种瞬态启动诱变（TIM）。我们得出结论，这些错误配对引发的模板滑动事件需要在下一轮DNA合成之前通过MutSβ进行MMR，以防止模板链中未配对的胞嘧啶的缺失。

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引用次数: 0

Dss1 facilitates Rad51 recruitment downstream of BRCA2/Brh2 in response to DNA damage Dss1在响应DNA损伤时促进BRCA2/Brh2下游的Rad51募集。

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2026-02-01 Epub Date: 2026-01-22 DOI: 10.1016/j.dnarep.2026.103923

Louise Juhl , Linea Busch , Jonas Bagge , Ruiqi Xu , Milorad Kojic , Mira Milisavljevic , Vibe H. Oestergaard , William K. Holloman , Michael Lisby

Homologous recombination (HR) is a major pathway for repair of DNA double-strand breaks (DSB), recovery of broken replication forks and formation of meiotic crossovers. HR provides a mechanism to precisely repair damaged DNA in a template-dependent process. The defining step in HR is homologous strand exchange directed by the RecA-related recombinase Rad51. BRCA2 and Brh2, the BRCA2 orthologue in Ustilago maydis, enable recombinational repair of DNA by controlling Rad51. In turn, Dss1, a small intrinsically disordered protein that binds to the C-terminal region of BRCA2/Brh2, regulates BRCA2/Brh2. In the present study, we dissect the interdependency of HR proteins for recruitment to DNA-damage induced foci using fluorescence microscopy and genetics. In U. maydis, Brh2 and Dss1 colocalize at DNA damage-induced foci. Dss1 recruitment to foci is dependent on interaction with full-length Brh2 and Dss1-Brh2 interaction is required for resistance to DNA damage. Further, Dss1 is required for Rad51 and Rec2 focus formation. Interestingly, we find that Rad52 is required for Brh2, Rec2 and Dss1 focus formation. In avian DT40 cells, we likewise show that endogenously tagged DSS1 redistributes into subnuclear foci in response to DNA damaging agents. However, DSS1 foci rarely colocalize with BRCA2 foci. Finally, Dss1 focus formation is inhibited by treatment with the proteasome inhibitor MG132, in both U. maydis and DT40 cells, suggesting a role of ubiquitin in homology-dependent repair.

同源重组（HR）是DNA双链断裂（DSB）修复、断裂复制叉恢复和减数分裂交叉形成的主要途径。HR提供了一种在模板依赖过程中精确修复受损DNA的机制。HR的决定性步骤是由reca相关重组酶Rad51引导的同源链交换。黑穗病菌BRCA2同源基因BRCA2和Brh2通过控制Rad51实现DNA的重组修复。反过来，Dss1，一种结合BRCA2/Brh2 c端区域的小的内在无序蛋白，调节BRCA2/Brh2。在本研究中，我们使用荧光显微镜和遗传学分析了HR蛋白在dna损伤诱导的病灶招募中的相互依赖性。在美国，Brh2和Dss1在DNA损伤诱导的病灶上共定位。Dss1向病灶的募集依赖于与全长Brh2的相互作用，Dss1-Brh2相互作用是抵抗DNA损伤所必需的。此外，Dss1是Rad51和Rec2焦点形成所必需的。有趣的是，我们发现Rad52是Brh2， Rec2和Dss1焦点形成所必需的。在禽类DT40细胞中，我们同样发现内源性标记的DSS1在DNA损伤剂的作用下重新分布到亚核病灶。然而，DSS1位点很少与BRCA2位点共定位。最后，在U. maydis和DT40细胞中，蛋白酶体抑制剂MG132可以抑制Dss1病灶的形成，这表明泛素在同源依赖性修复中的作用。

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引用次数: 0

Editorial: DNA crosslink repair: From molecules to mankind 社论：DNA交联修复：从分子到人类。

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2026-02-01 Epub Date: 2026-01-29 DOI: 10.1016/j.dnarep.2026.103927

Penny Jeggo , Puck Knipscheer , Peter J. McHugh

引用次数: 0

Tribute to life and science of Grigory (Gosha) Dianov 向格里戈里·迪亚诺夫的生命和科学致敬。

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2026-02-01 Epub Date: 2026-01-30 DOI: 10.1016/j.dnarep.2026.103925

Alexander V. Mazin , Andrei Kuzminov , Murat Saparbaev , Svetlana Khoronenkova , Jason Parsons , Sarah Allinson

引用次数: 0

Search, verify and excise-lesion recognition in NER 在NER中搜索、验证和切除病变识别

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2026-02-01 Epub Date: 2026-01-12 DOI: 10.1016/j.dnarep.2026.103922

Jochen Kuper, Caroline Kisker

Nucleotide excison repair (NER) is a highly versatile template-based DNA repair mechanism that can address lesions ranging from cyclo butane pyrimdine dimers, to cisplatinum crosslinks, and bulky adducts like acetyl amino flourenes. Eukaryotic NER employs more than thirty different proteins that coordinate and facilitate the search, verification, incision, and DNA re-synthesis of the various lesions with extremely high precision. High resolution structures of key complexes combined with biochemistry and computational biology have greatly enhanced our understanding of the NER process. In this review we will highlight recent discoveries in NER research concerning lesion search and handover of complex assemblies, lesion verification, and potential mechanisms providing the signal for incision with a focus on structural biology.

核苷酸切除修复（NER）是一种高度通用的基于模板的DNA修复机制，可以解决从环丁烷嘧啶二聚体到顺铂交联和大体积加合物如乙酰基氨基芴的损伤。真核生物NER使用超过30种不同的蛋白质，以极高的精度协调和促进各种病变的搜索、验证、切割和DNA重新合成。关键配合物的高分辨率结构与生物化学和计算生物学相结合，极大地增强了我们对NER过程的理解。在这篇综述中，我们将重点介绍最近在NER研究中的发现，包括病变搜索和复杂组件的移交、病变验证以及为切口提供信号的潜在机制，重点是结构生物学。

引用次数: 0

A special issue: DNA damage response in disease and therapy 特刊：疾病和治疗中的DNA损伤反应。

IF 2.7 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2026-02-01 Epub Date: 2026-01-22 DOI: 10.1016/j.dnarep.2026.103924

Guo-Min Li, Zhao-Qi Wang

引用次数: 0

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