Polo-like kinase 1 inhibits DNA damage response during mitosis

Cell Cycle. 2015;14(2):219-31. doi: 10.4161/15384101.2014.977067.

Abstract

In response to genotoxic stress, cells protect their genome integrity by activation of a conserved DNA damage response (DDR) pathway that coordinates DNA repair and progression through the cell cycle. Extensive modification of the chromatin flanking the DNA lesion by ATM kinase and RNF8/RNF168 ubiquitin ligases enables recruitment of various repair factors. Among them BRCA1 and 53BP1 are required for homologous recombination and non-homologous end joining, respectively. Whereas mechanisms of DDR are relatively well understood in interphase cells, comparatively less is known about organization of DDR during mitosis. Although ATM can be activated in mitotic cells, 53BP1 is not recruited to the chromatin until cells exit mitosis. Here we report mitotic phosphorylation of 53BP1 by Plk1 and Cdk1 that impairs the ability of 53BP1 to bind the ubiquitinated H2A and to properly localize to the sites of DNA damage. Phosphorylation of 53BP1 at S1618 occurs at kinetochores and in cytosol and is restricted to mitotic cells. Interaction between 53BP1 and Plk1 depends on the activity of Cdk1. We propose that activity of Cdk1 and Plk1 allows spatiotemporally controlled suppression of 53BP1 function during mitosis.

Keywords: 53BP1; 53BP1, p53 binding protein 1; ATM, ataxia telangiectasia mutated kinase; BRCA1, breast cancer type 1 susceptibility protein; Cdk, cyclin dependent kinase; DDR, DNA damage response; DNA damage response; H2AX, histone variant H2AX; IR – ionizing radiation; MDC1, mediator of DNA damage checkpoint protein 1; NCS – neocarzinostatin; NZ – nocodazole; PTIP, PAX transactivation activation domain-interacting protein; Plk1, Polo-like kinase 1; Polo like kinase 1; RIF1, Rap1-interacting factor 1 homolog; RNAi, RNA interference; RNF168, RING finger protein 168; RNF8, RING finger protein 8; mitosis; phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CDC2 Protein Kinase / metabolism
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line, Tumor
  • DNA Damage / radiation effects
  • DNA Repair*
  • Gamma Rays
  • HeLa Cells
  • Histones / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / antagonists & inhibitors
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Kinetochores / metabolism
  • Mitosis*
  • Phosphorylation
  • Protein Structure, Tertiary
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Tumor Suppressor p53-Binding Protein 1
  • Ubiquitination

Substances

  • Cell Cycle Proteins
  • Histones
  • Intracellular Signaling Peptides and Proteins
  • Proto-Oncogene Proteins
  • RNA, Small Interfering
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • Protein-Serine-Threonine Kinases
  • polo-like kinase 1
  • CDC2 Protein Kinase