Aurora kinase B dependent phosphorylation of 53BP1 is required for resolving merotelic kinetochore-microtubule attachment errors during mitosis.
Aurora kinase B dependent phosphorylation of 53BP1 is required for resolving merotelic kinetochore-microtubule attachment errors during mitosis.
复制标题
53BP1 的极光激酶 B 依赖性磷酸化对于解决有丝分裂过程中的动粒-微管附着错误是必需的
DOI：
10.18632/oncotarget.16225
复制
发表时间：
2017-07-25
期刊：
影响因子：
--
通讯作者：
Hegde ML
中科院分区：
文献类型：
--
作者：
Wang H;Peng B;Pandita RK;Engler DA;Matsunami RK;Xu X;Hegde PM;Butler BE;Pandita TK;Mitra S;Xu B;Hegde ML
在有丝分裂过程中，在解决着丝粒-微管附着错误方面的缺陷与与癌症发生相关的染色体不稳定以及对癌症治疗的抵抗有关。在此，我们首次报道了肿瘤抑制因子p53结合蛋白1(53BP1)在丝氨酸1342(S1342)处被极光激酶B在体外和人类细胞中磷酸化，这是53BP1在运动中心最佳募集所必需的。此外，53BP1染色通常定位于外部着丝粒，当着丝粒附着时，与有丝分裂着丝粒相关的动蛋白一起延伸到整个着丝粒。PS1342-53BP1的动粒结合对于有效地解决分型连接是必不可少的，分型连接是一种自发的动粒-微管连接错误，通常会导致非整倍体。在癌细胞和原代细胞中，53BP1的缺失总是导致滞后染色体事件、微核形成和非整倍体的显著增加，这是由于异位野生型53BP1可以阻止这一点，而非磷化的S1342A突变体则不能阻止这一点。因此，我们证明了53BP1在有丝分裂过程中维持忠实的染色体分离的一种新的DNA损伤无关功能。
Defects in resolving kinetochore-microtubule attachment mistakes during mitosis is linked to chromosome instability associated with carcinogenesis as well as resistance to cancer therapy. Here we report for the first time that tumor suppressor p53-binding protein 1 (53BP1) is phosphorylated at serine 1342 (S1342) by Aurora kinase B both in vitro and in human cells, which is required for optimal recruitment of 53BP1 at kinetochores. Furthermore, 53BP1 staining normally localized on the outer kinetochore, extended to the whole kinetochore when it is merotelically-attached, in concert with mitotic centromere-associated kinesin. Kinetochore-binding of pS1342-53BP1 is essential for efficient resolving of merotelic attachment, a spontaneous kinetochore-microtubule connection error that usually causes aneuploidy. Consistently, loss of 53BP1 results in significant increase in lagging chromosome events, micronuclei formation and aneuploidy, due to the unresolved merotely in both cancer and primary cells, which is prevented by ectopic wild type 53BP1 but not by the nonphophorylable S1342A mutant. We thus document a novel DNA damage-independent function of 53BP1 in maintaining faithful chromosome segregation during mitosis.