Plk1 Phosphorylation of Mre11 Antagonizes the DNA Damage Response

Cancer Res. 2017 Jun 15;77(12):3169-3180. doi: 10.1158/0008-5472.CAN-16-2787. Epub 2017 May 16.

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.

MeSH terms

  • Animals
  • Antineoplastic Agents
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • Comet Assay
  • DNA Damage / physiology*
  • DNA-Binding Proteins / metabolism*
  • Electrophoretic Mobility Shift Assay
  • Gene Expression Regulation, Neoplastic / physiology
  • Heterografts
  • Humans
  • MRE11 Homologue Protein
  • Mice
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Phosphorylation
  • Phthalazines
  • Piperazines
  • Polo-Like Kinase 1
  • Protein Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Xenopus laevis

Substances

  • Antineoplastic Agents
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • MRE11 protein, human
  • Phthalazines
  • Piperazines
  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • MRE11 Homologue Protein
  • olaparib