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ATM-phosphorylated SPOP contributes to 53BP1 exclusion from chromatin during DNA replication
Science Advances ( IF 11.7 ) Pub Date : 2021-06-18 , DOI: 10.1126/sciadv.abd9208
Dejie Wang 1, 2 , Jian Ma 3, 4 , Maria Victoria Botuyan 1 , Gaofeng Cui 1 , Yuqian Yan 1 , Donglin Ding 1 , Yingke Zhou 1 , Eugene W Krueger 1 , Jiang Pei 5 , Xiaosheng Wu 6 , Liguo Wang 7 , Huadong Pei 8, 9 , Mark A McNiven 1, 10 , Dingwei Ye 3, 4 , Georges Mer 1, 10, 11 , Haojie Huang 1, 10, 12
Affiliation  

53BP1 activates nonhomologous end joining (NHEJ) and inhibits homologous recombination (HR) repair of DNA double-strand breaks (DSBs). Dissociation of 53BP1 from DSBs and consequent activation of HR, a less error-prone pathway than NHEJ, helps maintain genome integrity during DNA replication; however, the underlying mechanisms are not fully understood. Here, we demonstrate that E3 ubiquitin ligase SPOP promotes HR during S phase of the cell cycle by excluding 53BP1 from DSBs. In response to DNA damage, ATM kinase–catalyzed phosphorylation of SPOP causes a conformational change in SPOP, revealed by x-ray crystal structures, that stabilizes its interaction with 53BP1. 53BP1-bound SPOP induces polyubiquitination of 53BP1, eliciting 53BP1 extraction from chromatin by a valosin-containing protein/p97 segregase complex. Our work shows that SPOP facilitates HR repair over NHEJ during DNA replication by contributing to 53BP1 removal from chromatin. Cancer-derived SPOP mutations block SPOP interaction with 53BP1, inducing HR defects and chromosomal instability.



中文翻译:


ATM 磷酸化 SPOP 导致 DNA 复制过程中 53BP1 被染色质排除



53BP1 激活非同源末端连接 (NHEJ) 并抑制 DNA 双链断裂 (DSB) 的同源重组 (HR) 修复。 53BP1 从 DSB 解离并随后激活 HR,这是一种比 NHEJ 更不易出错的途径,有助于在 DNA 复制过程中保持基因组完整性;然而,其根本机制尚未完全了解。在这里,我们证明 E3 泛素连接酶 SPOP 通过从 DSB 中排除 53BP1 来促进细胞周期 S 期的 HR。 X 射线晶体结构显示,为了响应 DNA 损伤,ATM 激酶催化的 SPOP 磷酸化会导致 SPOP 发生构象变化,从而稳定其与 53BP1 的相互作用。 53BP1 结合的 SPOP 诱导 53BP1 多泛素化,从而通过含有缬洛新的蛋白/p97 分离酶复合物从染色质中提取 53BP1。我们的工作表明,在 DNA 复制过程中,SPOP 通过促进 53BP1 从染色质上去除,促进了 NHEJ 上的 HR 修复。癌症衍生的 SPOP 突变会阻断 SPOP 与 53BP1 的相互作用,从而诱导 HR 缺陷和染色体不稳定。

更新日期:2021-06-18
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