title: p53 coordinates base excision repair to prevent genomic instability.
abstract: 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.
authors.affiliation: CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Department of Oncology, Old Road Campus Research Building, OX37DQ Oxford, UK.
authors.forename: Mattia
authors.initials: M
authors.lastname: Poletto
authors.affiliation: CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Department of Oncology, Old Road Campus Research Building, OX37DQ Oxford, UK.
authors.forename: Arnaud J
authors.initials: AJ
authors.lastname: Legrand
authors.affiliation: CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Department of Oncology, Old Road Campus Research Building, OX37DQ Oxford, UK.
authors.forename: Sally C
authors.initials: SC
authors.lastname: Fletcher
authors.affiliation: CRUK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Department of Oncology, Old Road Campus Research Building, OX37DQ Oxford, UK Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Lavrenteva 10, 630090 Novosibirsk, Russia grigory.dianov@oncology.ox.ac.uk.
authors.forename: Grigory L
authors.initials: GL
authors.lastname: Dianov
mesh_terms: D002478:Cells, Cultured; D053904:DNA Breaks, Single-Stranded; D004260:DNA Repair; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000096:biosynthesis / Q000235:genetics; D015536:Down-Regulation; D042822:Genomic Instability; D006801:Humans; D016329:Sp1 Transcription Factor / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016329:Sp1 Transcription Factor; D016159:Tumor Suppressor Protein p53; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase