DNA Repair最新文献

英文中文

Role of NEIL1 in genome maintenance NEIL1在基因组维持中的作用

IF 3 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-02-19 DOI: 10.1016/j.dnarep.2025.103820

Amanda K. McCullough , Irina G. Minko , Michael M. Luzadder , Jamie T. Zuckerman , Vladimir L. Vartanian , Pawel Jaruga , Miral Dizdaroglu , R. Stephen Lloyd

Phylogenetic analyses of DNA glycosylases that function in the initiation step of base excision repair reveal a high degree of conservation within the genes encoding Nei-like DNA glycosylase 1 (NEIL1). In concert with other glycosylases, this enzyme is an important player in cleansing both nuclear and mitochondrial genomes of a wide variety of damaged DNA bases. The relative efficiency of NEIL1 to catalyze release of ring-opened formamido-pyrimidines (Fapy) and alkylated-Fapy adducts, multiple ring-saturated pyrimidines, secondary oxidation products of 8-oxoguanine, and psoralen-derived crosslinks is augmented by pre-mRNA editing at codon 242, resulting in cells containing both NEIL1-Lys242 and edited Arg242. The biological significance of NEIL1 was revealed through investigations of mutagenesis and carcinogenesis in murine models, primarily using aflatoxin B₁ (AFB₁) as a genotoxicant challenge, which forms stable AFB₁-FapyGua adducts. Specifically, Neil1 knockout mice were > 3-fold more susceptible to AFB₁-induced carcinogenesis as compared to either wild-type or nucleotide excision repair-deficient Xpa^-/- mice. These data are well-supported by duplex sequencing analyses that showed increased AFB₁-induced mutagenesis in Neil1^-/- mice relative to wild-type or Xpa^-/- mice. Given the biological impact of Neil1 deficiencies in cancer, metabolic syndrome, and neurodegeneration, extrapolation to humans carrying single nucleotide polymorphisms (SNPs) in NEIL1 may suggest that deleterious variants could increase disease risk following various genotoxicant exposures. To address this hypothesis, we have undertaken a systematic characterization of human NEIL1 SNP variants that are distributed throughout the world. The goal of this review is to provide comprehensive analyses of the biochemistry and biology of NEIL1.

对碱基切除修复起始步骤中起作用的DNA糖基酶的系统发育分析显示，编码Nei-like DNA糖基酶1 （NEIL1）的基因高度保守。与其他糖基酶一起，该酶在清除核和线粒体基因组中各种受损DNA碱基方面起着重要作用。NEIL1催化开环甲酰胺嘧啶（Fapy）和烷基化Fapy加合物、多环饱和嘧啶、8-氧鸟嘌呤的二次氧化产物和补骨脂素衍生交联释放的相对效率通过pre-mRNA在密码子242上的编辑而增强，导致细胞中同时含有NEIL1- lys242和编辑过的Arg242。NEIL1的生物学意义是通过小鼠模型的诱变和致癌研究揭示的，主要是利用黄曲霉毒素B1 （AFB1）作为基因毒性攻击，形成稳定的AFB1- fapygua加合物。具体来说，与野生型或核苷酸切除修复缺陷的Xpa-/-小鼠相比，Neil1敲除小鼠对afb1诱导的癌变的易感性增加了>； 3倍。这些数据得到了双工测序分析的很好支持，该分析显示，相对于野生型或Xpa-/-小鼠，afb1诱导的Neil1-/-小鼠突变增加。鉴于Neil1缺陷在癌症、代谢综合征和神经退行性疾病中的生物学影响，推断携带Neil1单核苷酸多态性（snp）的人类可能表明，有害变异可能会增加各种基因毒物暴露后的疾病风险。为了解决这一假设，我们对分布在世界各地的人类NEIL1 SNP变体进行了系统的表征。本文综述的目的是对NEIL1的生物化学和生物学进行全面的分析。

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引用次数: 0

The effect of methylation and hydroxymethylation of cytosine on activity and fidelity of Pol λ and Pol β 胞嘧啶的甲基化和羟甲基化对 Pol λ 和 Pol β 的活性和保真度的影响

IF 3 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-02-17 DOI: 10.1016/j.dnarep.2025.103815

Evgeniy S. Shilkin , Daria V. Petrova , Alexander A. Kruchinin , Dmitry O. Zharkov , Alena V. Makarova

Сytosine methylation in CpG dinucleotides is the most common epigenetic mark in human cells. Under active demethylation process 5-methylcytosine (mC) can be converted to 5-hydroxymethylcytosine (hmC). Cytosine methylation increases the risk of adjacent nucleotide damage, including the oxidation of guanine. DNA polymerases might encounter mC and hmC during DNA repair or translesion synthesis. Here, we analyze the activity of X-family polymerases Pol β and Pol λ opposite mC and hmC as well as opposite 8-oxoG adjacent to mC in the TCG context. We demonstrate that hmC has no pronounced effect on Pol β and Pol λ activity while cytosine methylation moderately suppresses the efficiency of dGMP incorporation by Pol β but not Pol λ. Pol λ was not affected by + 2 cytosine methylation when synthesizing across 8-oxoG. In contrast, cytosine methylation slightly increased incorporation of dCMP opposite 8-oxoG adjacent to mC but reduced the extension of the 8-oxoG:C pair by Pol β.

Сytosine CpG二核苷酸的甲基化是人类细胞中最常见的表观遗传标记。在活性去甲基化过程中，5-甲基胞嘧啶（mC）可转化为5-羟甲基胞嘧啶（hmC）。胞嘧啶甲基化增加了邻近核苷酸损伤的风险，包括鸟嘌呤的氧化。DNA聚合酶在DNA修复或翻译合成过程中可能遇到mC和hmC。在此，我们分析了在TCG环境下mC和hmC对面的x家族聚合酶Pol β和Pol λ以及mC附近的8-oxoG的活性。我们发现hmC对Pol β和Pol λ活性没有明显的影响，而胞嘧啶甲基化适度抑制了Pol β掺入dGMP的效率，但对Pol λ没有影响。通过8-oxoG合成时，Pol λ不受+ 2胞嘧啶甲基化的影响。相比之下，胞嘧啶甲基化略微增加了8-oxoG对面的dCMP在mC附近的掺入，但减少了Pol β对8-oxoG:C对的延伸。

引用次数: 0

Pathological modulation of genome maintenance by cancer/testes antigens (CTAs) 癌/睾丸抗原（cta）对基因组维持的病理调节

IF 3 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-02-16 DOI: 10.1016/j.dnarep.2025.103818

Cyrus Vaziri , Karly Forker , Xingyuan Zhang , Di Wu , Pei Zhou , Jessica L. Bowser

The Cancer Testis Antigens (CTAs) are a group of germ cell proteins that are absent from normal somatic cells yet aberrantly expressed in many cancer cells. When mis-expressed in cancer cells, many CTAs promote tumorigenic characteristics including genome instability, DNA damage tolerance and therapy resistance. Here we highlight some of the CTAs for which their roles in genome maintenance in cancer cells are well established. We consider three broad CTA categories: (1) Melanoma Antigens (MAGEs) (2) Mitotic CTAs and (3) CTAs with roles in meiotic homologous recombination. Many cancer cells rely on CTAs to tolerate intrinsic and therapy-induced genotoxic stress. Therefore, CTAs represent molecular vulnerabilities of cancer cells and may provide opportunities for therapy. Owing to their high-level expression in tumors and absence from normal somatic cells, CTA-directed therapies could have a high level of specificity and would likely be devoid of side-effect toxicity.

癌睾丸抗原（cta）是一组生殖细胞蛋白，在正常体细胞中不存在，但在许多癌细胞中异常表达。当在癌细胞中错误表达时，许多cta会促进致瘤性特征，包括基因组不稳定性、DNA损伤耐受性和治疗耐药性。在这里，我们重点介绍了一些cta，它们在癌细胞基因组维持中的作用已经得到了很好的证实。我们考虑了三大类CTA:(1)黑色素瘤抗原（mage）；(2)有丝分裂CTA；(3)在减数分裂同源重组中起作用的CTA。许多癌细胞依靠cta来耐受内在的和治疗诱导的基因毒性应激。因此，cta代表了癌细胞的分子脆弱性，可能为治疗提供机会。由于cta在肿瘤中的高水平表达和正常体细胞的缺失，cta定向治疗可能具有高水平的特异性，并且可能没有副作用毒性。

引用次数: 0

Therapeutic targeting of mismatch repair proteins in triplet repeat expansion diseases 错配修复蛋白在三联体重复扩增疾病中的靶向治疗

IF 3 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-02-15 DOI: 10.1016/j.dnarep.2025.103817

Paulina Marzec , Madeleine Richer , Robert S. Lahue

Triplet repeat expansion diseases are a class of ∼20 inherited neurological disorders. Many of these diseases are debilitating, sometimes fatally so, and they have unfortunately proved difficult to treat. New compelling evidence shows that somatic repeat expansions in some diseases are essential to the pathogenic process, accelerating the age of onset and the rate of disease progression. Inhibiting somatic repeat expansions, therefore, provides a therapeutic opportunity to delay or block disease onset and/or slow progression. Several key aspects enhance the appeal of this therapeutic approach. First, the proteins responsible for promoting expansions are known from human genetics and model systems, obviating the need for lengthy target searches. They include the mismatch repair proteins MSH3, PMS1 and MLH3. Second, inhibiting or downregulating any of these three proteins is attractive due to their good safety profiles. Third, having three potential targets helps mitigate risk. Fourth, another protein, the nuclease FAN1, protects against expansions; in principle, increasing FAN1 activity could be therapeutic. Fifth, therapies aimed at inhibiting somatic repeat expansions could be used against several diseases that display this shared mechanistic feature, offering the opportunity for one treatment against multiple diseases. This review will address the underlying findings and the recent therapeutic advances in targeting MSH3, PMS1, MLH3 and FAN1 in triplet repeat expansion diseases.

三联体重复扩增病是一类~ 20种遗传性神经系统疾病。这些疾病中有许多使人衰弱，有时甚至是致命的，不幸的是，它们被证明是难以治疗的。新的令人信服的证据表明，在某些疾病中，体细胞重复扩增对致病过程至关重要，加速了发病年龄和疾病进展速度。因此，抑制体细胞重复扩增提供了延迟或阻断疾病发作和/或缓慢进展的治疗机会。几个关键方面增强了这种治疗方法的吸引力。首先，负责促进扩增的蛋白质是从人类遗传学和模型系统中已知的，从而避免了冗长的目标搜索的需要。它们包括错配修复蛋白MSH3、PMS1和MLH3。其次，抑制或下调这三种蛋白质中的任何一种都具有良好的安全性。第三，有三个潜在目标有助于降低风险。第四，另一种蛋白质，即核酸酶FAN1，可以防止扩增；原则上，增加FAN1活性可能具有治疗作用。第五，旨在抑制体细胞重复扩增的疗法可用于治疗几种表现出这种共同机制特征的疾病，从而为一种治疗多种疾病提供了机会。本文综述了针对MSH3、PMS1、MLH3和FAN1在三联体重复扩增疾病中的潜在发现和最新治疗进展。

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引用次数: 0

USP1 in regulation of DNA repair pathways USP1参与DNA修复途径的调控。

IF 3 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-02-01 DOI: 10.1016/j.dnarep.2025.103807

Amir Mahdi Mazloumi Aboukheili, Helen Walden

Ubiquitin-specific protease 1 (USP1) is the founding member of the family of cysteine proteases that catalyse hydrolysis of the isopeptide bond between ubiquitin and targets. USP1 is often overexpressed in various cancers, and expression levels correlate with poor prognosis. USP1 and its partner USP1-associated Factor 1 (UAF1) are required for deubiquitinating monoubiquitin signals in DNA interstrand crosslink repair, and in Translesion synthesis, among others, and both proteins are subject to multiple regulations themselves. This review covers recent findings on the mechanisms and functions of USP1 in DNA repair, its regulation, and its potential as a target for therapeutic intervention.

泛素特异性蛋白酶1 （USP1）是半胱氨酸蛋白酶家族的创始成员，催化水解泛素和靶标之间的异肽键。USP1在多种癌症中经常过表达，表达水平与预后不良相关。USP1及其伙伴USP1-associated Factor 1 （UAF1）是DNA链间交联修复、翻译合成等过程中去泛素化单泛素信号所必需的，这两种蛋白本身都受到多种调控。本文综述了USP1在DNA修复中的机制和功能、调控及其作为治疗干预靶点的潜力等方面的最新发现。

引用次数: 0

Lawrence H. Thompson: A life of bikes, birds, and DNA repair (1941–2024) 劳伦斯·h·汤普森：自行车、鸟和DNA修复的生活（1941-2024）。

IF 3 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-02-01 DOI: 10.1016/j.dnarep.2025.103813

Keith W. Caldecott

引用次数: 0

Single-molecule toxicogenomics: Optical genome mapping of DNA-damage in nanochannel arrays 单分子毒物基因组学：纳米通道阵列中dna损伤的光学基因组图谱。

IF 3 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-02-01 DOI: 10.1016/j.dnarep.2025.103808

Tahir Detinis Zur , Sapir Margalit , Jonathan Jeffet , Assaf Grunwald , Sivan Fishman , Zuzana Tulpová , Yael Michaeli , Jasline Deek , Yuval Ebenstein

Quantitative genomic mapping of DNA damage may provide insights into the underlying mechanisms of damage and repair. Sequencing based approaches are bound to the limitations of PCR amplification bias and read length which hamper both the accurate quantitation of damage events and the ability to map them to structurally complex genomic regions. Optical Genome mapping in arrays of parallel nanochannels allows physical extension and genetic profiling of millions of long genomic DNA fragments, and has matured to clinical utility for characterization of complex structural aberrations in cancer genomes. Here we present a new mapping modality, Repair-Assisted Damage Detection - Optical Genome Mapping (RADD-OGM), a method for single-molecule level mapping of DNA damage on a genome-wide scale. Leveraging ultra-long reads to assemble the complex structure of a sarcoma cell-line genome, we mapped the genomic distribution of oxidative DNA damage, identifying regions more susceptible to DNA oxidation. We also investigated DNA repair by allowing cells to repair chemically induced DNA damage, pinpointing locations of concentrated repair activity, and highlighting variations in repair efficiency. Our results showcase the potential of the method for toxicogenomic studies, mapping the effect of DNA damaging agents such as drugs and radiation, as well as following specific DNA repair pathways by selective induction of DNA damage. The facile integration with optical genome mapping enables performing such analyses even in highly rearranged genomes such as those common in many cancers, a challenging task for sequencing-based approaches.

DNA损伤的定量基因组图谱可能为损伤和修复的潜在机制提供见解。基于测序的方法受到PCR扩增偏差和读取长度的限制，这既阻碍了损伤事件的准确定量，也阻碍了将它们映射到结构复杂的基因组区域的能力。在平行纳米通道阵列中的光学基因组图谱允许对数百万长的基因组DNA片段进行物理扩展和遗传分析，并且已经成熟到临床应用于癌症基因组中复杂结构畸变的表征。在这里，我们提出了一种新的作图方式，修复辅助损伤检测-光学基因组作图（rad - ogm），一种在全基因组范围内进行DNA损伤单分子水平作图的方法。利用超长读取来组装肉瘤细胞系基因组的复杂结构，我们绘制了氧化DNA损伤的基因组分布，确定了更容易受到DNA氧化的区域。我们还通过允许细胞修复化学诱导的DNA损伤，精确定位集中修复活性的位置，并突出修复效率的变化来研究DNA修复。我们的研究结果显示了该方法在毒性基因组学研究中的潜力，可以绘制DNA损伤剂（如药物和辐射）的影响，以及通过选择性诱导DNA损伤来遵循特定的DNA修复途径。光学基因组图谱的便捷整合，甚至可以对高度重排的基因组（如许多癌症中常见的基因组）进行这样的分析，这对于基于测序的方法来说是一项具有挑战性的任务。

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引用次数: 0

Active genome integrity 活性基因组完整性

IF 3 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-02-01 DOI: 10.1016/j.dnarep.2025.103816

Sukesh R. Bhaumik

引用次数: 0

To divide or not to divide? NAC8 (SOG1) as a key regulator of DNA damage response in barley (Hordeum vulgare L.) 分还是不分？na8 （SOG1）作为大麦DNA损伤反应的关键调控因子

IF 3 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-02-01 DOI: 10.1016/j.dnarep.2025.103810

Miriam Szurman-Zubrzycka , Anna Kocjan , Emilia Spałek , Monika Gajecka , Paulina Jędrzejek , Małgorzata Nawrot , Iwona Szarejko , Jolanta Kwasniewska

We identified several new TILLING mutants of barley (Hordeum vulgare L.) with missense mutations in the HvNAC8 gene, a homolog of the SUPPRESSOR OF GAMMA RESPONSE 1 (SOG1) gene in Arabidopsis thaliana. In Arabidopsis, SOG1 is the primary regulator of the DNA Damage Response (DDR) pathway. We aimed to transfer this knowledge to barley, an agriculturally important crop. Our detailed analysis of the hvnac8.k mutant revealed an impaired DDR pathway. The hvnac8.k mutant accumulates DNA damage under genotoxic stress induced by zeocin, but it also shows increased DNA damage under normal growth conditions. Despite this, the frequency of dividing cells in the root meristem of the mutant treated with zeocin is much less affected than in the wild type. This suggests that the mutant bypasses the typical DDR regulation, where cell division is halted to allow DNA repair following damage. We also analyzed our mutant under aluminum (Al³⁺) stress. Aluminum ions, present in acidic soils that constitute approximately 50 % of arable land, are a common stressor that significantly reduce barley yield. Al³ ⁺ is known to cause DNA damage and activate DDR. Consequently, we aimed to assess whether the hvnac8.k phenotype could confer a beneficial effect under aluminum stress, a widespread agronomic challenge. Our findings suggest that modulation of the DDR pathway has the potential to improve aluminum tolerance in barley.

我们发现了几个新的大麦（Hordeum vulgare L.） TILLING突变体，其HvNAC8基因是拟南芥中GAMMA反应抑制基因1 （SOG1）的同源基因。在拟南芥中，SOG1是DNA损伤反应（DDR）途径的主要调节因子。我们的目标是将这些知识转移到大麦上，这是一种重要的农业作物。我们对hvnac8的详细分析。k突变体显示DDR通路受损。hvnac8。k突变体在zeocin诱导的基因毒性胁迫下积累DNA损伤，但在正常生长条件下也表现出增加的DNA损伤。尽管如此，与野生型相比，经zeocin处理的突变体根分生组织中分裂细胞的频率受到的影响要小得多。这表明突变体绕过了典型的DDR调节，在这种调节中，细胞分裂被停止以允许DNA在损伤后进行修复。我们还分析了铝（Al³+）胁迫下的突变体。铝离子存在于酸性土壤中，约占耕地面积的50% %，是大麦产量显著降低的常见应激源。已知Al³ ⁺会导致DNA损伤并激活DDR。因此，我们的目的是评估hvnac8。在铝胁迫这一广泛的农艺挑战下，K表型可能会带来有益的影响。我们的研究结果表明，DDR通路的调节有可能提高大麦的铝耐受性。

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The Ataxia-telangiectasia mutated (ATM) is the most important gene for repairing the DNA in Myelodysplastic Neoplasm 共济失调毛细血管扩张突变（ATM）是骨髓增生异常肿瘤中修复DNA最重要的基因。

IF 3 3区生物学 Q2 GENETICS & HEREDITY

DNA Repair

Pub Date : 2025-02-01 DOI: 10.1016/j.dnarep.2024.103803

Ronald Feitosa Pinheiro , João Vitor Caetano Goes , Leticia Rodrigues Sampaio , Roberta Taiane Germano de Oliveira , Sheila Coelho Soares Lima , Cristiana Libardi Miranda Furtado , Daniela de Paula Borges , Marilia Braga Costa , Cristiane da Silva Monte , Natalia Feitosa Minete , Silvia Maria Meira Magalhães , Howard Lopes Ribeiro Junior

Myelodysplastic Neoplasm (MDS) is a cancer associated with aging, often leading to acute myeloid leukemia (AML). One of its hallmarks is hypermethylation, particularly in genes responsible for DNA repair. This study aimed to evaluate the methylation and mutation status of DNA repair genes (single-strand - XPA, XPC, XPG, CSA, CSB and double-strand - ATM, BRCA1, BRCA2, LIG4, RAD51) in MDS across three patient cohorts (Cohort A-56, Cohort B-100, Cohort C-76), using methods like pyrosequencing, real-time PCR, immunohistochemistry, and mutation screening. Results showed that XPA had higher methylation in low-risk MDS compared to high-risk MDS. For double-strand repair genes, ATM displayed higher methylation in patients who transformed to AML (p = 0.016). ATM gene expression was downregulated in MDS compared to controls (p = 0.042). When patients were classified according to the WHO 2022 guidelines, ATM expression progressively decreased from low-risk subtypes (e.g., Hypoplastic MDS) to high-risk MDS and AML. Patients who transformed to AML had a higher 5mC/5hmC ratio compared to those who didn’t (p = 0.045). Additionally, poor cytogenetic risk patients had higher tissue methylation scores than those with good risk (p = 0.035). Analysis using the cBioPortal platform identified ATM as the most frequently mutated DNA repair gene, with various mutations, such as frameshift and missense, most of which were classified as oncogenic. The findings suggest that ATM is frequently silenced or downregulated in MDS due to methylation or mutations, contributing to the progression to AML. This highlights ATM's potential role in the disease’s advancement and as a target for future therapeutic strategies.

骨髓增生异常肿瘤（MDS）是一种与衰老相关的癌症，常导致急性髓性白血病（AML）。它的一个特征是高度甲基化，特别是在负责DNA修复的基因中。本研究旨在评估三个患者队列（队列A-56、队列B-100、队列C-76） MDS中DNA修复基因（单链- XPA、XPC、XPG、CSA、CSB和双链- ATM、BRCA1、BRCA2、LIG4、RAD51）的甲基化和突变状态，采用磷酸氢测序、实时PCR、免疫组织化学和突变筛选等方法。结果显示，与高危MDS相比，低危MDS中XPA的甲基化程度更高。对于双链修复基因，ATM在转化为AML的患者中显示出更高的甲基化（p = 0.016）。与对照组相比，MDS中ATM基因表达下调（p = 0.042）。当患者按照WHO 2022指南进行分类时，ATM的表达从低风险亚型（如发育不全MDS）逐渐下降到高风险MDS和AML。转化为AML的患者的5mC/5hmC比值高于未转化为AML的患者（p = 0.045）。此外，低细胞遗传风险患者的组织甲基化评分高于高风险患者（p = 0.035）。利用cbiopportal平台的分析发现，ATM是最常发生突变的DNA修复基因，其突变多种多样，如移码和错义，其中大多数被归类为致癌基因。研究结果表明，由于甲基化或突变，ATM在MDS中经常沉默或下调，从而导致AML的进展。这突出了ATM在疾病进展中的潜在作用以及作为未来治疗策略的目标。

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