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 2 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.

中文翻译：

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FIRRM/C1orf112 响应 DNA 链间交联介导同源重组中间体的解析

如果不修复，DNA 链间交联 (ICL) 将成为 DNA 复制和转录的主要障碍。细胞对 ICL 的反应需要协调各种 DNA 修复机制。响应 ICL 生成的同源重组 (HR) 中间体需要通过结构选择性核酸内切酶进行有效且及时的转换。我们对这一过程的精确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来绘制 ICL 反应所涉及的机制，并确定 FIRRM/C1orf112 是维持基因组稳定性不可或缺的因素。FIRRM 缺陷导致对 ICL 诱导化合物过敏，SG 期间 DNA 损伤累积2细胞周期的阶段和染色体畸变，并引发先前在 HR 缺陷肿瘤中观察到的独特突变特征。此外，FIRRM 被招募到 ICL，控制 MUS81 染色质负载，从而影响 HR 中间体的分辨率。小鼠 FIRRM 缺陷会导致早期胚胎死亡并加速肿瘤形成。因此，FIRRM 在 DNA 复制过程中对 ICL 的响应中发挥着关键作用。