LAP2α 通过协助 RPA 在受损染色质上的沉积来维护基因组的完整性。

IF 12.3 1区生物学 Q1 Agricultural and Biological Sciences Genome Biology Pub Date : 2022-02-28 DOI:10.1186/s13059-022-02638-6

Kaiwen Bao, Qi Zhang, Shuai Liu, Nan Song, Qiushi Guo, Ling Liu, Shanshan Tian, Jihui Hao, Yi Zhu, Kai Zhang, Ding Ai, Jie Yang, Zhi Yao, Roland Foisner, Lei Shi

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引用次数: 0

摘要

背景：复制蛋白 A（RPA）包被的单链 DNA（ssDNA）是 DNA 损伤反应中基因组维持因子招募和交换的关键平台。然而，ssDNA-RPA中间体的形成是如何调控的仍不清楚：结果：我们在此报告了片层相关蛋白LAP2α与RPA的物理关联，LAP2α通过LAP2α和RPA1之间的物理接触优先促进RPA在受损染色质上的沉积。重要的是，LAP2α 促进 RPA 与 ssDNA 结合，在保护复制叉、激活 ATR 和修复受损 DNA 方面发挥了关键作用。我们进一步证明，LAP2α促进的RPA负载在受损染色质上的偏好取决于多聚ADP-核糖聚合酶PARP1，而不是多聚（ADP-核糖）结合：我们的研究从机理上揭示了DNA损伤时RPA的沉积，并揭示了LAP2α的基因组保护作用。

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LAP2α preserves genome integrity through assisting RPA deposition on damaged chromatin.

Background: Single-stranded DNA (ssDNA) coated with replication protein A (RPA) acts as a key platform for the recruitment and exchange of genome maintenance factors in DNA damage response. Yet, how the formation of the ssDNA-RPA intermediate is regulated remains elusive.

Results: Here, we report that the lamin-associated protein LAP2α is physically associated with RPA, and LAP2α preferentially facilitates RPA deposition on damaged chromatin via physical contacts between LAP2α and RPA1. Importantly, LAP2α-promoted RPA binding to ssDNA plays a critical role in protection of replication forks, activation of ATR, and repair of damaged DNA. We further demonstrate that the preference of LAP2α-promoted RPA loading on damaged chromatin depends on poly ADP-ribose polymerase PARP1, but not poly(ADP-ribosyl)ation.

Conclusions: Our study provides mechanistic insight into RPA deposition in response to DNA damage and reveals a genome protection role of LAP2α.

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来源期刊

Genome Biology BIOTECHNOLOGY & APPLIED MICROBIOLOGY-GENETICS & HEREDITY

CiteScore

25.50

自引率

3.30%

发文量

审稿时长

14 weeks

期刊介绍： Genome Biology is a leading research journal that focuses on the study of biology and biomedicine from a genomic and post-genomic standpoint. The journal consistently publishes outstanding research across various areas within these fields. With an impressive impact factor of 12.3 (2022), Genome Biology has earned its place as the 3rd highest-ranked research journal in the Genetics and Heredity category, according to Thomson Reuters. Additionally, it is ranked 2nd among research journals in the Biotechnology and Applied Microbiology category. It is important to note that Genome Biology is the top-ranking open access journal in this category. In summary, Genome Biology sets a high standard for scientific publications in the field, showcasing cutting-edge research and earning recognition among its peers.