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研究揭示断裂诱导复制的调控机制
作者:小柯机器人 发布时间:2021/1/22 16:16:55

美国爱荷华大学Anna Malkova、贝勒医学院Grzegorz Ira等研究人员合作揭示断裂诱导复制的调控机制。该研究于2021年1月20日在线发表于国际一流学术期刊《自然》。

研究人员表示,断裂诱导复制(BIR)能够修复DNA的一端双链断裂,类似于由复制断裂或端粒侵蚀形成的断裂,并且已与癌症和其他人类疾病的基因组不稳定性的启动有关。先前的研究已经定义了BIR所需的酶;但是,由于技术局限性,无法理解初始和延伸的BIR合成,以及如何通过已知的复制障碍物进行D环迁移。

研究人员使用了一种新开发的测定法发现,BIR合成在链入侵后立即开始,并且进行的速度比S期复制慢。如果没有引发酶,则引导链的合成会有效地启动,但无法进行超过30千个碱基的合成,这表明必须有引发酶才能稳定新生的引导链。DNA合成可以在没有Pif1或Pol32的情况下启动,但不能有效进行。间隙端粒DNA能够破坏并终止BIR进程,并且BIR的启动受到与转录水平成正比的转录的抑制。BIR和转录之间的冲突导致诱变和染色体重排,其水平超过了正常复制过程中转录引起的不稳定性。

总之,这些结果提供了对BIR机制以及BIR如何导致基因组不稳定的基本见解。

附:英文原文

Title: Tracking break-induced replication shows that it stalls at roadblocks

Author: Liping Liu, Zhenxin Yan, Beth A. Osia, Jerzy Twarowski, Luyang Sun, Juraj Kramara, Rosemary S. Lee, Sandeep Kumar, Rajula Elango, Hanzeng Li, Weiwei Dang, Grzegorz Ira, Anna Malkova

Issue&Volume: 2021-01-20

Abstract: Break-induced replication (BIR) repairs one-ended double-strand breaks in DNA similar to those formed by replication collapse or telomere erosion, and it has been implicated in the initiation of genome instability in cancer and other human diseases1,2. Previous studies have defined the enzymes that are required for BIR1–5; however, understanding of initial and extended BIR synthesis, and of how the migrating D-loop proceeds through known replication roadblocks, has been precluded by technical limitations. Here we use a newly developed assay to show that BIR synthesis initiates soon after strand invasion and proceeds more slowly than S-phase replication. Without primase, leading strand synthesis is initiated efficiently, but is unable to proceed beyond 30 kilobases, suggesting that primase is needed for stabilization of the nascent leading strand. DNA synthesis can initiate in the absence of Pif1 or Pol32, but does not proceed efficiently. Interstitial telomeric DNA disrupts and terminates BIR progression, and BIR initiation is suppressed by transcription proportionally to the transcription level. Collisions between BIR and transcription lead to mutagenesis and chromosome rearrangements at levels that exceed instabilities induced by transcription during normal replication. Together, these results provide fundamental insights into the mechanism of BIR and how BIR contributes to genome instability. A method of tracking break-induced replication reveals the details of this repair process and shows that it can be impaired by certain genomic elements and by transcription.

DOI: 10.1038/s41586-020-03172-w

Source: https://www.nature.com/articles/s41586-020-03172-w

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html