Plk1 Phosphorylation of Mre11 Antagonizes the DNA Damage Response

Cancer Research
Zhiguo LiXiaoqi Liu

Abstract

The mitotic kinase Plk1 contributes to the DNA damage response (DDR) by targeting multiple factors downstream of the core responder kinase ATM/ATR. In this study, we show that Polo-like kinase 1 (Plk1) also phosphorylates key factors upstream of ATM/ATR and regulates their DDR-related functions. Plk1 phosphorylated Mre11, a component of the Mre11/Rad50/Nbs1 (MRN) complex, at serine 649 (S649) during DDR. Phosphorylation of Mre11-S649 by Plk1 primed subsequent CK2-mediated phosphorylation at Mre11-serine 688 (S688). Phosphorylation of Mre11 at S649/S688 inhibited loading of the MRN complex to damaged DNA, leading to both premature DNA damage checkpoint termination and inhibition of DNA repair. Tumors expressing phosphomimetic Mre11 were more sensitive to the PARP inhibitor olaparib, compared with those expressing unphosphorylatable Mre11, suggesting that patients with elevated Plk1 expression might benefit from olaparib treatment. Cancer Res; 77(12); 3169-80. ©2017 AACR.

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Citations

Sep 14, 2017·The Journal of Biological Chemistry·Zhiguo LiXiaoqi Liu
Jan 15, 2019·Current Genetics·Héloïse Coutelier, Zhou Xu
Oct 17, 2019·Frontiers in Oncology·Yan-Yang WangRen Zhao
Oct 18, 2020·Cancers·Chelsea E CunninghamFranco J Vizeacoumar
Mar 22, 2018·Cancer Research·Zhiguo LiXiaoqi Liu
Nov 2, 2019·Prostaglandins & Other Lipid Mediators·Marco RahmStefanie M Hauck
Aug 30, 2021·Biochemical Pharmacology·Styliani IliakiInna S Afonina
Dec 4, 2021·Science Advances·Laura J BaileyAidan J Doherty

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