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p53 coordinates base excision repair to prevent genomic instability

Mattia Poletto1, Arnaud J Legrand1, Sally C Fletcher1

  • 1CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Department of Oncology, Old Road Campus Research Building, OX37DQ Oxford, UK.

Nucleic Acids Research
|January 17, 2016
PubMed

Insights

DNA repair is crucial for genomic stability. This study reveals that the p53 protein coordinates DNA base excision repair (BER) by regulating APE1 endonuclease, preventing genomic instability in healthy cells.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cancer Research

Background:

  • DNA damage is continuously generated by mutagens.
  • The Base Excision Repair (BER) pathway repairs most DNA lesions.
  • Unrepaired DNA single-strand breaks (SSBs) can lead to genomic instability.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of the BER pathway.
  • To investigate the role of p53 in coordinating BER.
  • To understand how BER dysfunction contributes to genomic instability.

Main Methods:

  • Investigated the impact of unrepaired SSBs on BER components.
  • Utilized p53 functional assays and APE1 endonuclease activity measurements.
  • Analyzed DNA strand break accumulation and genomic instability markers.

Main Results:

  • Accumulation of unrepaired SSBs induces p53/Sp1-dependent downregulation of APE1.
  • Impaired p53 function results in APE1 overexpression and increased DNA strand breaks.
  • p53 dysfunction leads to genomic instability due to failed BER coordination.

Conclusions:

  • p53 plays a critical, previously unrecognized role in coordinating BER.
  • Dysfunction of this p53-mediated BER coordination mechanism contributes to genomic instability in p53-inactivated cells, common in cancer.

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