Laboratory for Cell Biology and Genetics, Rockefeller University, New York, NY 10065, USA.
Science. 2013 Feb 8;339(6120):700-4. doi: 10.1126/science.1231573. Epub 2013 Jan 10.
The choice between double-strand break (DSB) repair by either homology-directed repair (HDR) or nonhomologous end joining (NHEJ) is tightly regulated. Defects in this regulation can induce genome instability and cancer. 53BP1 is critical for the control of DSB repair, promoting NHEJ, and inhibiting the 5' end resection needed for HDR. Using dysfunctional telomeres and genome-wide DSBs, we identify Rif1 as the main factor used by 53BP1 to impair 5' end resection. Rif1 inhibits resection involving CtIP, BLM, and Exo1; limits accumulation of BRCA1/BARD1 complexes at sites of DNA damage; and defines one of the mechanisms by which 53BP1 causes chromosomal abnormalities in Brca1-deficient cells. These data establish Rif1 as an important contributor to the control of DSB repair by 53BP1.
双链断裂 (DSB) 的修复选择要么通过同源定向修复 (HDR)，要么通过非同源末端连接 (NHEJ)，这一选择受到严格调控。这种调控的缺陷会导致基因组不稳定和癌症。53BP1 对于 DSB 修复的控制至关重要，它促进 NHEJ，并抑制 HDR 所需的 5'端切除。利用功能失调的端粒和全基因组 DSB，我们确定 Rif1 是 53BP1 用于损害 5'端切除的主要因素。 Rif1 抑制涉及 CtIP、BLM 和 Exo1 的切除；限制 BRCA1/BARD1 复合物在 DNA 损伤部位的积累；并定义了 53BP1 在 Brca1 缺陷细胞中导致染色体异常的机制之一。这些数据确立了 Rif1 是 53BP1 控制 DSB 修复的一个重要因素。
