Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, NY 10065, USA.
Proc Natl Acad Sci U S A. 2013 Feb 5;110(6):2146-51. doi: 10.1073/pnas.1222617110. Epub 2013 Jan 23.
Tumor suppressor p53-binding protein 1 (53BP1) regulates the repair of dysfunctional telomeres lacking the shelterin protein TRF2 by promoting their mobility, their nonhomologous end-joining (NHEJ), and, as we show here, by blocking 5' resection by CtIP. We report that these functions of 53BP1 required its N-terminal ATM/ATR target sites and its association with H4K20diMe, but not the BRCT domain, the GAR domain, or the binding of 53BP1 to dynein. A mutant lacking the oligomerization domain (53BP1(oligo)) was only modestly impaired in promoting NHEJ of dysfunctional telomeres and showed no defect with regard to the repression of CtIP. This 53BP1(oligo) allele was previously found to be unable to support class switch recombination or to promote radial chromosome formation in PARP1 inhibitor-treated Brca1-deficient cells. The data therefore support two conclusions. First, the requirements for 53BP1 in mediating NHEJ at dysfunctional telomeres and in class switch recombination are not identical. Second, 53BP1-dependent repression of CtIP at double-strand breaks (DSBs) is unlikely to be sufficient for the generation of radial chromosomes in PARP1 inhibitor-treated Brca1-deficient cells.
肿瘤抑制因子 p53 结合蛋白 1（53BP1）通过促进其移动、非同源末端连接（NHEJ），并如我们在此处所示，通过阻止 CtIP 进行 5' 切除，来调节缺乏庇护蛋白 TRF2 的功能失调端粒的修复。我们报告称，53BP1 的这些功能需要其 N 端 ATM/ATR 靶位和与 H4K20diMe 的结合，但不需要 BRCT 结构域、GAR 结构域或 53BP1 与动力蛋白的结合。缺乏寡聚结构域的突变体（53BP1(oligo)）在促进功能失调端粒的 NHEJ 中仅略有缺陷，并且在抑制 CtIP 方面没有缺陷。先前发现该 53BP1(oligo)等位基因无法支持类别转换重组或在 PARP1 抑制剂处理的 BRCA1 缺陷细胞中促进放射状染色体形成。因此，数据支持两个结论。首先，53BP1 在介导功能失调端粒处的 NHEJ 和类别转换重组中的要求并不相同。其次，53BP1 依赖性 CtIP 在双链断裂（DSB）处的抑制不太可能足以在 PARP1 抑制剂处理的 BRCA1 缺陷细胞中产生放射状染色体。
