Mitosis Inhibits DNA Double-Strand Break Repair to Guard Against Telomere Fusions
Mitosis Inhibits DNA Double-Strand Break Repair to Guard Against Telomere Fusions
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DOI：
10.1126/science.1248024
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发表时间：
2014-04-11
期刊：
影响因子：
56.9
通讯作者：
Durocher, Daniel
中科院分区：
文献类型：
--
作者：
Orthwein, Alexandre;Fradet-Turcotte, Amelie;Durocher, Daniel
有丝分裂细胞抑制DNA双链断裂（DSB）修复，但这种抑制背后的原理仍然未知。在这里，我们解开了有丝分裂如何阻止DSB修复，并确定修复重新激活的后果。有丝分裂激酶磷酸化E3泛素连接酶RNF8和非同源末端连接因子53BP1，以抑制它们向DSB侧翼染色质的募集。RNF8和53BP1在有丝分裂DSB位点积累的恢复激活DNA修复，但矛盾的是，是有害的。异常控制的有丝分裂DSB修复导致极光B激酶依赖的姐妹端粒融合，产生双着丝粒染色体和非整倍体，特别是在存在外源性遗传毒性应激的情况下。我们的结论是，有丝分裂DSB修复的能力，不稳定的基因组解释了其抑制在有丝分裂过程中的必要性，主要是由于有丝分裂端粒的融合潜力。
Mitotic cells inactivate DNA double-strand break (DSB) repair, but the rationale behind this suppression remains unknown. Here, we unravel how mitosis blocks DSB repair and determine the consequences of repair reactivation. Mitotic kinases phosphorylate the E3 ubiquitin ligase RNF8 and the nonhomologous end joining factor 53BP1 to inhibit their recruitment to DSB-flanking chromatin. Restoration of RNF8 and 53BP1 accumulation at mitotic DSB sites activates DNA repair but is, paradoxically, deleterious. Aberrantly controlled mitotic DSB repair leads to Aurora B kinase-dependent sister telomere fusions that produce dicentric chromosomes and aneuploidy, especially in the presence of exogenous genotoxic stress. We conclude that the capacity of mitotic DSB repair to destabilize the genome explains the necessity for its suppression during mitosis, principally due to the fusogenic potential of mitotic telomeres.