Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Mol Cell. 2012 Apr 27;46(2):125-35. doi: 10.1016/j.molcel.2012.02.015. Epub 2012 Mar 22.
Brca1 is required for DNA repair by homologous recombination (HR) and normal embryonic development. Here we report that deletion of the DNA damage response factor 53BP1 overcomes embryonic lethality in Brca1-nullizygous mice and rescues HR deficiency, as measured by hypersensitivity to polyADP-ribose polymerase (PARP) inhibition. However, Brca1,53BP1 double-deficient cells are hypersensitive to DNA interstrand crosslinks (ICLs), indicating that BRCA1 has an additional role in DNA crosslink repair that is distinct from HR. Disruption of the nonhomologous end-joining (NHEJ) factor, Ku, promotes DNA repair in Brca1-deficient cells; however deletion of either Ku or 53BP1 exacerbates genomic instability in cells lacking FANCD2, a mediator of the Fanconi anemia pathway for ICL repair. BRCA1 therefore has two separate roles in ICL repair that can be modulated by manipulating NHEJ, whereas FANCD2 provides a key activity that cannot be bypassed by ablation of 53BP1 or Ku.
Brca1 对于同源重组（HR）和正常胚胎发育的 DNA 修复是必需的。在这里，我们报告说，删除 DNA 损伤反应因子 53BP1 可以克服 Brca1 纯合缺失小鼠的胚胎致死性，并挽救 HR 缺陷，如对聚 ADP-核糖聚合酶（PARP）抑制的敏感性增加所测量的。然而，Brca1、53BP1 双缺失细胞对 DNA 链间交联（ICLs）敏感，表明 BRCA1 在 DNA 交联修复中具有不同于 HR 的额外作用。非同源末端连接（NHEJ）因子 Ku 的破坏促进了 BRCA1 缺陷细胞中的 DNA 修复；然而，Ku 或 53BP1 的缺失都会加剧缺乏 FANCD2 的细胞中的基因组不稳定性，FANCD2 是 Fanconi 贫血途径中 ICL 修复的介质。因此，BRCA1 在 ICL 修复中具有两个独立的作用，可以通过操纵 NHEJ 来调节，而 FANCD2 提供了一个关键的活性，不能通过 53BP1 或 Ku 的消融来绕过。
