53BP1-dependent robust localized KAP-1 phosphorylation is essential for heterochromatic DNA double-strand break repair
53BP1-dependent robust localized KAP-1 phosphorylation is essential for heterochromatic DNA double-strand break repair
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DOI：
10.1038/ncb2017
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发表时间：
2010-02-01
影响因子：
21.3
通讯作者：
Goodarzi, Aaron A.
中科院分区：
文献类型：
--
作者：
Noon, Angela T.;Shibata, Atsushi;Goodarzi, Aaron A.
DNA双链断裂（DSB）触发ATM（共济失调毛细血管扩张突变）信号传导，并在错误修复或未修复时引发基因组重排和染色体片段化。尽管大多数DSB修复是ATM非依赖性的，但类似于15%的电离辐射（IR）诱导的断裂在缺乏ATM信号传导的情况下持续存在（1）。53 BP 1（p53结合蛋白1）促进ATM依赖性DSB修复，但在很大程度上是ATM激活或检查点阻滞。ATM通过磷酸化KAP-1（KRAB相关蛋白1，也称为TIF 1 β、TRIM 28或KRIP-1;参考文献2）促进异染色质内的DSB修复。在这里，我们表明，ATM信号介质蛋白MDC 1，RNF 8，RNF 168和53 BP 1也需要异染色质DSB修复。尽管KAP-1磷酸化对于53 BP 1介导的修复至关重要，但总体磷酸化KAP-1（pKAP-1）水平仅受到53 BP 1损失的适度影响。pKAP-1是瞬时泛核的，但也在异染色质中形成与γ H2 AX重叠的病灶。不形成53 BP 1灶的细胞，包括人RIDDLE（放射敏感性、免疫缺陷、畸形特征和学习困难）综合征细胞，不能形成pKAP-1灶。53 BP 1放大了Mre 11-NBS 1在后期修复DSB中的积累，集中了活性ATM，并导致了强大的局部pKAP-1。我们建议，电离辐射诱导的病灶（IRIF）空间集中ATM活动，以促进本地化的改变，否则抑制修复的染色质区域。
DNA double-strand breaks (DSBs) trigger ATM (ataxia telangiectasia mutated) signalling and elicit genomic rearrangements and chromosomal fragmentation if misrepaired or unrepaired. Although most DSB repair is ATM-independent, similar to 15% of ionizing radiation (IR)-induced breaks persist in the absence of ATM-signalling(1). 53BP1 (p53-binding protein 1) facilitates ATM-dependent DSB repair but is largely dispensable for ATM activation or checkpoint arrest. ATM promotes DSB repair within heterochromatin by phosphorylating KAP-1 (KRAB-associated protein 1, also known as TIF1 beta, TRIM28 or KRIP-1; ref. 2). Here, we show that the ATM signalling mediator proteins MDC1, RNF8, RNF168 and 53BP1 are also required for heterochromatic DSB repair. Although KAP-1 phosphorylation is critical for 53BP1-mediated repair, overall phosphorylated KAP-1 (pKAP-1) levels are only modestly affected by 53BP1 loss. pKAP-1 is transiently pan-nuclear but also forms foci overlapping with gamma H2AX in heterochromatin. Cells that do not form 53BP1 foci, including human RIDDLE (radiosensitivity, immunodeficiency, dysmorphic features and learning difficulties) syndrome cells, fail to form pKAP-1 foci. 53BP1 amplifies Mre11-NBS1 accumulation at late-repairing DSBs, concentrating active ATM and leading to robust, localized pKAP-1. We propose that ionizing-radiation induced foci (IRIF) spatially concentrate ATM activity to promote localized alterations in regions of chromatin otherwise inhibitory to repair.