title: A role for the p53 tumour suppressor in regulating the balance between homologous recombination and non-homologous end joining.
abstract: Loss of p53, a transcription factor activated by cellular stress, is a frequent event in cancer. The role of p53 in tumour suppression is largely attributed to cell fate decisions. Here, we provide evidence supporting a novel role for p53 in the regulation of DNA double-strand break (DSB) repair pathway choice. 53BP1, another tumour suppressor, was initially identified as p53 Binding Protein 1, and has been shown to inhibit DNA end resection, thereby stimulating non-homologous end joining (NHEJ). Yet another tumour suppressor, BRCA1, reciprocally promotes end resection and homologous recombination (HR). Here, we show that in both human and mouse cells, the absence of p53 results in impaired 53BP1 focal recruitment to sites of DNA damage induced by ionizing radiation. This effect is largely independent of cell cycle phase and the extent of DNA damage. In p53-deficient cells, diminished localization of 53BP1 is accompanied by a reciprocal increase in BRCA1 recruitment to DSBs. Consistent with these findings, we demonstrate that DSB repair via NHEJ is abrogated, while repair via homology-directed repair (HDR) is stimulated. Overall, we propose that in addition to its role as an 'effector' protein in the DNA damage response, p53 plays a role in the regulation of DSB repair pathway choice.
authors.affiliation: Genome Stability Laboratory, Centre for Chromosome Biology and School of Natural Science, Biomedical Science Building, National University of Ireland Galway, Dangan, Ireland.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Moureau
authors.affiliation: Genome Stability Laboratory, Centre for Chromosome Biology and School of Natural Science, Biomedical Science Building, National University of Ireland Galway, Dangan, Ireland.
authors.forename: Janna
authors.initials: J
authors.lastname: Luessing
authors.affiliation: Genome Stability Laboratory, Centre for Chromosome Biology and School of Natural Science, Biomedical Science Building, National University of Ireland Galway, Dangan, Ireland.
authors.forename: Emma Christina
authors.initials: EC
authors.lastname: Harte
authors.affiliation: Genome Stability Laboratory, Centre for Chromosome Biology and School of Natural Science, Biomedical Science Building, National University of Ireland Galway, Dangan, Ireland.
authors.forename: Muriel
authors.initials: M
authors.lastname: Voisin
authors.affiliation: Genome Stability Laboratory, Centre for Chromosome Biology and School of Natural Science, Biomedical Science Building, National University of Ireland Galway, Dangan, Ireland noel.lowndes@nuigalway.ie.
authors.forename: Noel Francis
authors.identifier: http://orcid.org/0000-0002-3216-4427
authors.initials: NF
authors.lastname: Lowndes
keywords: 53BP1; BRCA1; DNA double-strand break repair; homologous recombination r; non-homologous end joining; p53