Plk1 phosphorylation of Mre11 antagonizes the DNA damage response

Zhiguo Li, Jie Li, Yifan Kong, Shan Yan, Nihal Ahmad, Xiaoqi Liu

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

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.

Original languageEnglish
Pages (from-to)3169-3180
Number of pages12
JournalCancer Research
Volume77
Issue number12
DOIs
StatePublished - Jun 15 2017

Bibliographical note

Publisher Copyright:
© 2017 American Association for Cancer Research.

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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