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FIRRM/C1orf112 介导 DNA 链间交联反应中同源重组中间体的解决。

FIRRM/C1orf112 mediates resolution of homologous recombination intermediates in response to DNA interstrand crosslinks.

机构信息

Division of Biochemistry, Netherlands Cancer Institute, Amsterdam, Netherlands.

Oncode Institute, Amsterdam, Netherlands.

出版信息

Sci Adv. 2023 Jun 2;9(22):eadf4409. doi: 10.1126/sciadv.adf4409. Epub 2023 May 31.

DOI:10.1126/sciadv.adf4409
PMID:37256941
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10413679/
Abstract

DNA interstrand crosslinks (ICLs) pose a major obstacle for DNA replication and transcription if left unrepaired. The cellular response to ICLs requires the coordination of various DNA repair mechanisms. Homologous recombination (HR) intermediates generated in response to ICLs, require efficient and timely conversion by structure-selective endonucleases. Our knowledge on the precise coordination of this process remains incomplete. Here, we designed complementary genetic screens to map the machinery involved in the response to ICLs and identified FIRRM/C1orf112 as an indispensable factor in maintaining genome stability. FIRRM deficiency leads to hypersensitivity to ICL-inducing compounds, accumulation of DNA damage during S-G phase of the cell cycle, and chromosomal aberrations, and elicits a unique mutational signature previously observed in HR-deficient tumors. In addition, FIRRM is recruited to ICLs, controls MUS81 chromatin loading, and thereby affects resolution of HR intermediates. FIRRM deficiency in mice causes early embryonic lethality and accelerates tumor formation. Thus, FIRRM plays a critical role in the response to ICLs encountered during DNA replication.

摘要

DNA 链间交联 (ICLs) 如果不修复，会对 DNA 复制和转录造成严重阻碍。细胞对 ICLs 的反应需要各种 DNA 修复机制的协调。为了应对 ICLs 而产生的同源重组 (HR) 中间体，需要结构选择性核酸内切酶进行有效且及时的转换。我们对这一过程的确切协调的了解仍然不完整。在这里，我们设计了互补的遗传筛选，以绘制参与 ICLs 反应的机制图谱，并鉴定出 FIRRM/C1orf112 是维持基因组稳定性所必需的因素。FIRRM 缺陷导致对 ICL 诱导化合物敏感，细胞周期 S-G 期 DNA 损伤积累，以及染色体异常，并引发以前在 HR 缺陷肿瘤中观察到的独特突变特征。此外，FIRRM 被招募到 ICLs 上，控制 MUS81 染色质加载，从而影响 HR 中间体的解析。小鼠 FIRRM 缺陷导致早期胚胎致死和肿瘤形成加速。因此，FIRRM 在应对 DNA 复制过程中遇到的 ICLs 中发挥着关键作用。

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