MERIT40 cooperates with BRCA2 to resolve DNA interstrand cross-links.
MERIT40 cooperates with BRCA2 to resolve DNA interstrand cross-links.
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DOI：
10.1101/gad.264192.115
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发表时间：
2015-09-15
影响因子：
10.5
通讯作者：
Greenberg RA
中科院分区：
文献类型：
--
作者：
Jiang Q;Paramasivam M;Aressy B;Wu J;Bellani M;Tong W;Seidman MM;Greenberg RA
Jiang等人发现Merit 40 −/−小鼠对DNA链间交联（ICL）表现出明显的超敏反应，但对全身照射则没有。这项研究暗示MERIT 40在ICL修复的最早阶段，并定义了RAP 80复合物依赖性泛素识别和FA-BRCA ICL修复网络之间的特定功能相互作用。MERIT 40是RAP 80泛素识别复合物的重要组成部分，它将BRCA 1靶向DNA损伤位点。虽然这种复合物是BRCA 1灶形成所必需的，但其在DNA修复中的生理作用仍然是个谜，因为它与经典DNA修复机制的关系也是如此。令人惊讶的是，我们发现Merit 40 −/−小鼠对DNA链间交联（ICL）表现出明显的超敏反应，但对全身照射却没有。MERIT 40在FANCD 2之前被迅速募集到ICL病变，并且Merit 40-null细胞表现出延迟的ICL脱钩，伴随着减少的末端切除和ICL损伤处的同源重组。有趣的是，Merit 40突变加剧了ICL诱导的染色体不稳定性的背景下，伴随Brca 2缺陷，但不与Fancd 2突变。这些发现暗示MERIT 40在ICL修复的最早阶段，并定义了RAP 80复合物依赖性泛素识别和范可尼贫血（FA）-BRCA ICL修复网络之间的特定功能相互作用。
Jiang et al. found that Merit40−/− mice displayed marked hypersensitivity to DNA interstrand cross-links (ICLs) but not whole-body irradiation. This study implicates MERIT40 in the earliest stages of ICL repair and defines specific functional interactions between RAP80 complex-dependent ubiquitin recognition and the FA–BRCA ICL repair network. MERIT40 is an essential component of the RAP80 ubiquitin recognition complex that targets BRCA1 to DNA damage sites. Although this complex is required for BRCA1 foci formation, its physiologic role in DNA repair has remained enigmatic, as has its relationship to canonical DNA repair mechanisms. Surprisingly, we found that Merit40−/− mice displayed marked hypersensitivity to DNA interstrand cross-links (ICLs) but not whole-body irradiation. MERIT40 was rapidly recruited to ICL lesions prior to FANCD2, and Merit40-null cells exhibited delayed ICL unhooking coupled with reduced end resection and homologous recombination at ICL damage. Interestingly, Merit40 mutation exacerbated ICL-induced chromosome instability in the context of concomitant Brca2 deficiency but not in conjunction with Fancd2 mutation. These findings implicate MERIT40 in the earliest stages of ICL repair and define specific functional interactions between RAP80 complex-dependent ubiquitin recognition and the Fanconi anemia (FA)–BRCA ICL repair network.