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DNA constantly undergoes chemical modification due to endogenous and exogenous mutagens. The DNA base excision repair (BER) pathway is the frontline mechanism handling the majority of these lesions, and primarily involves a DNA incision and subsequent resealing step. It is imperative that these processes are extremely well-coordinated as unrepaired DNA single strand breaks (SSBs) can be converted to DNA double strand breaks during replication thus triggering genomic instability. However, the mechanism(s) governing the BER process are poorly understood. Here we show that accumulation of unrepaired SSBs triggers a p53/Sp1-dependent downregulation of APE1, the endonuclease responsible for the DNA incision during BER. Importantly, we demonstrate that impaired p53 function, a characteristic of many cancers, leads to a failure of the BER coordination mechanism, overexpression of APE1, accumulation of DNA strand breaks and results in genomic instability. Our data provide evidence for a previously unrecognized mechanism for coordination of BER by p53, and its dysfunction in p53-inactivated cells.

Original publication

DOI

10.1093/nar/gkw015

Type

Journal article

Journal

Nucleic Acids Res

Publication Date

20/04/2016

Volume

44

Pages

3165 - 3175

Keywords

Cells, Cultured, DNA Breaks, Single-Stranded, DNA Repair, DNA-(Apurinic or Apyrimidinic Site) Lyase, Down-Regulation, Genomic Instability, Humans, Sp1 Transcription Factor, Tumor Suppressor Protein p53