Department of Pharmacy, College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan, Gyeonggi-do, Korea.
Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
Oncogene. 2017 Feb 16;36(7):966-978. doi: 10.1038/onc.2016.263. Epub 2016 Aug 1.
Although 53BP1 has been established well as a mediator in DNA damage response, its function in mitosis is not clearly understood. We found that 53BP1 is a mitotic-binding partner of the kinases Plk1 and AuroraA, and that the binding with Plk1 increases the stability of 53BP1 by accelerating its interaction with the deubiquitinase USP7. Depletion of 53BP1 induces mitotic defects such as chromosomal missegregation, misorientation of spindle poles and the generation of extra centrosomes, which is similar phenotype to USP7-knockdown cells. In addition, 53BP1 depletion reduces the levels of p53 and centromere protein F (CENPF), interacting proteins of 53BP1. These phenotypes induced by 53BP1 depletion were rescued by expression of wild-type or phosphomimic mutant 53BP1 but not by expression of a dephosphomimic mutant. We propose that phosphorylation of 53BP1 at S380 accelerates complex formation with USP7 and CENPF to regulate their stability, thus having a crucial role in proper centrosome positioning, chromosomal alignment, and centrosome number.
虽然 53BP1 已被充分确立为 DNA 损伤反应的介质，但它在有丝分裂中的功能尚不清楚。我们发现 53BP1 是激酶 Plk1 和 AuroraA 的有丝分裂结合伴侣，并且与 Plk1 的结合通过加速其与去泛素酶 USP7 的相互作用来增加 53BP1 的稳定性。53BP1 的耗竭会诱导有丝分裂缺陷，如染色体错分、纺锤体极的错位和额外中心体的产生，这与 USP7 敲低细胞的表型相似。此外，53BP1 的耗竭会降低 p53 和着丝粒蛋白 F（CENPF）的水平，这是 53BP1 的相互作用蛋白。53BP1 耗竭引起的这些表型可以通过表达野生型或磷酸模拟突变型 53BP1 得到挽救，但不能通过表达去磷酸模拟突变型得到挽救。我们提出，53BP1 在 S380 处的磷酸化加速了与 USP7 和 CENPF 的复合物形成，从而调节它们的稳定性，因此在正确的中心体定位、染色体排列和中心体数量方面起着至关重要的作用。
