Role of 53BP1 oligomerization in regulating double-strand break repair
Role of 53BP1 oligomerization in regulating double-strand break repair
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DOI：
10.1073/pnas.1222617110
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发表时间：
2013-02-05
影响因子：
11.1
通讯作者：
de Lange, Titia
中科院分区：
文献类型：
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作者：
Lottersberger, Francisca;Bothmer, Anne;de Lange, Titia
肿瘤抑制因子p53结合蛋白1（53 BP 1）通过促进端粒的移动性、非同源末端连接（NHEJ）以及阻断CtIP的5'端切除来调节缺乏shelterin蛋白TRF 2的功能障碍性端粒的修复。我们报告说，53 BP 1的这些功能需要其N-末端ATM/ATR靶位点及其与H4 K20 diMe的结合，而不是BRCT结构域，GAR结构域，或53 BP 1与动力蛋白的结合。缺乏寡聚化结构域的突变体（53 BP 1（oligo））在促进功能失调的端粒的NHEJ方面仅适度受损，并且在CtIP的抑制方面没有表现出缺陷。这53 BP 1 oligo等位基因先前被发现不能支持类转换重组或促进放射状染色体形成PARP 1的信使处理的Brca 1缺陷细胞。因此，数据支持两个结论。首先，53 BP 1在功能失调的端粒处介导NHEJ和在类别转换重组中的要求是不相同的。第二，53 BP 1依赖性抑制CtIP在双链断裂（DSBs）是不太可能足以产生放射状染色体在PARP 1受体处理的Brca 1缺陷细胞。
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 53BP1oligo 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.