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Nat Commun:浙江大学黄俊研究组揭示DNA双链断裂损伤被细胞识别并修复分子机制

摘要 : 2017年10月17日,国际学术权威刊物自然出版集团旗下子刊《Nature Communication》杂志在线发表了浙江大学生命科学研究院黄俊实验室题为“AUNIP/C1orf135 directs DNA double-strand breaks towards the homologous recombination repair pathway”的研究论文

2017年10月17日,国际学术权威刊物自然出版集团旗下子刊《Nature Communication》杂志在线发表了浙江大学生命科学研究院黄俊实验室题为“AUNIP/C1orf135 directs DNA double-strand breaks towards the homologous recombination repair pathway”的研究论文,论文阐明了AUNIP/C1orf135蛋白在识别并区分不同类型的DNA双链断裂损伤(double-strand breaks, DSBs)并选择正确的DSBs修复途径中的重要功能及作用机制。黄俊实验室博士生娄江曼和陈红霞博士为论文的共同第一作者,黄俊教授为论文的通讯作者。

DSBs是最具威胁的DNA损伤类型之一,如果不能及时修复或发生错误修复,则会导致基因突变、基因组不稳定以及肿瘤等重大疾病的发生。DSBs根据它末端的性质可以分为两种类型:双末端DSBs (Two-ended DSBs)和复制相关的单末端DSBs (Replication-associated one-ended DSBs)。DSBs主要通过非同源末端连接(non-homologous end-joining,NHEJ)和同源重组(homologous recombination,HR)这两种修复途径完成修复。研究表明,Two-ended DSBs主要通过NHEJ完成修复;而Replication-associated one-ended DSBs则只能通过HR完成修复。如果Replication-associated one-ended DSBs通过NHEJ完成修复,则会导致不同染色体之间的连接,进而引起translocation的发生以及基因组不稳定。然而,细胞如何识别并区分这两种不同类型的DSBs从而选择正确的DSBs修复途径还很不清楚。

黄俊实验室的研究发现AUNIP蛋白是一个重要的DSBs的识别因子。一方面,AUNIP通过优先结合Replication-associated one-ended DSBs从而区分Two-ended DSBs和Replication-associated one-ended DSBs。另一方面,AUNIP通过与HR关键起始蛋白CtIP直接相互作用从而优先招募CtIP蛋白到Replication-associated one-ended DSBs上,使得Replication-associated one-ended DSBs只能通过HR完成修复。与此同时,由于AUNIP蛋白结合Two-ended DSBs能力较弱,导致CtIP蛋白不能够被有效的招募到Two-ended DSBs位点,进而使得Two-ended DSBs主要通过NHEJ完成修复。该研究不仅阐明了DSBs修复途径的正确选择在维持基因组稳定以及抑制肿瘤发生过程中的重要作用,还将为今后对肿瘤的药物治疗提供新的分子靶标及理论支持。

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图:AUNIP识别不同的损伤类型并选择正确的修复途径的分子机制

原文链接:

AUNIP/C1orf135 directs DNA double-strand breaks towards the homologous recombination repair pathway

原文摘要:

DNA double-strand breaks (DSBs) are mainly repaired by either homologous recombination (HR) or non-homologous end-joining (NHEJ). Here, we identify AUNIP/C1orf135, a largely uncharacterized protein, as a key determinant of DSB repair pathway choice. AUNIP physically interacts with CtIP and is required for efficient CtIP accumulation at DSBs. AUNIP possesses intrinsic DNA-binding ability with a strong preference for DNA substrates that mimic structures generated at stalled replication forks. This ability to bind DNA is necessary for the recruitment of AUNIP and its binding partner CtIP to DSBs, which in turn drives CtIP-dependent DNA-end resection and HR repair. Accordingly, loss of AUNIP or ablation of its ability to bind to DNA results in cell hypersensitivity toward a variety of DSB-inducing agents, particularly those that induce replication-associated DSBs. Our findings provide new insights into the molecular mechanism by which DSBs are recognized and channeled to the HR repair pathway.

来源: Nature Communications 浏览次数:0

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