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Polo-like kinase 1 inhibits DNA damage response during mitosis

Jan Benada1, Kamila Burdová, Tomáš Lidak

  • 1a Department of Cancer Cell Biology; Institute of Molecular Genetics; Academy of Sciences of the Czech Republic ; Prague , Czech Republic.

Cell Cycle (Georgetown, Tex.)
|January 22, 2015
PubMed

Insights

During mitosis, cell division, specific kinases (Plk1 and Cdk1) phosphorylate 53BP1, a key DNA damage response protein. This phosphorylation temporarily suppresses 53BP1

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Genetics

Background:

  • The DNA damage response (DDR) pathway is crucial for maintaining genome integrity during genotoxic stress.
  • While DDR mechanisms in interphase cells are well-studied, their organization during mitosis remains less understood.
  • Key DDR factors like BRCA1 and 53BP1 are involved in DNA repair pathways such as homologous recombination and non-homologous end joining.

Purpose of the Study:

  • To investigate the regulation of the DNA damage response (DDR) during mitosis.
  • To elucidate the mechanisms controlling the function of 53BP1, a critical DNA repair protein, during cell division.

Main Methods:

  • Investigated the phosphorylation of 53BP1 during mitosis using cell-based assays.
  • Examined the interaction between 53BP1, Plk1, and Cdk1 in mitotic cells.
  • Assessed the impact of phosphorylation on 53BP1's ability to bind ubiquitinated H2A and localize to DNA damage sites.

Main Results:

  • Identified mitotic phosphorylation of 53BP1 by Plk1 and Cdk1 at specific sites (S1618), occurring at kinetochores and in the cytosol.
  • Demonstrated that this phosphorylation impairs 53BP1's binding to ubiquitinated H2A and its proper localization to DNA damage sites.
  • Showed that the interaction between 53BP1 and Plk1 is dependent on Cdk1 activity.

Conclusions:

  • Propose a model where Cdk1 and Plk1 activity spatiotemporally controls 53BP1 function during mitosis, suppressing its DNA repair role.
  • Mitotic phosphorylation of 53BP1 by Plk1 and Cdk1 serves as a regulatory mechanism to prevent its premature function during cell division.
  • Understanding this mitotic regulation of 53BP1 is essential for comprehending genome stability maintenance throughout the cell cycle.
Keywords:
53BP153BP1, p53 binding protein 1ATM, ataxia telangiectasia mutated kinaseBRCA1, breast cancer type 1 susceptibility proteinCdk, cyclin dependent kinaseDDR, DNA damage responseDNA damage responseH2AX, histone variant H2AXIR – ionizing radiationMDC1, mediator of DNA damage checkpoint protein 1NCS – neocarzinostatinNZ – nocodazolePTIP, PAX transactivation activation domain-interacting proteinPlk1, Polo-like kinase 1Polo like kinase 1RIF1, Rap1-interacting factor 1 homologRNAi, RNA interferenceRNF168, RING finger protein 168RNF8, RING finger protein 8mitosisphosphorylation

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