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.

How the Other Half Lives: What p53 Does When It Is Not Being a Transcription Factor

“…In the absence of p53, 53BP1 foci formation at damage sites following ionizing radiation is impaired. Instead, there is an increase in BRCA1 recruitment, and these changes are independent of the degree of damage or cell cycle stage [72]. Such a transcription-independent role for p53 in defining the choice of repair pathway has significant implications for tumorigenesis and tumor response to chemotherapy.…”

Dynamic recognition and repair of DNA complex damage

“…γH2AX is phosphorylated at serine 139 by ATM kinase upon the generation of a DSB. As a DSB marker, DSB damage can be analyzed by quantifying γH2AX foci, size, and quality (Lorat et al, 2016;Moureau et al, 2016 demonstrated that p53 binding protein 1 (53BP1) foci contain DSB sites (Schultz et al, 2000). XRCC1, a necessary factor for singlestrand break repair; Ku70, which plays a role in nonhomologous end joining (NHEJ); and Rad51, which functions in homologous recombination repair, are also known to participate in DNA damage repair (Schultz et al, 2000;Lord & Ashworth, 2012;Moureau et al, 2016;Whitehouse et al, 2001).…”

Both DNA binding domains of p53 are required for its ultra-rapid recruitment to sites of UV damage

“…p53 has been implicated in transcriptionally-independent regulation of different DNA repair 10 pathways like nucleotide-excision repair, base-excision repair and mismatch repair(3). P53 is also emerging as an important factor in regulating the balance between homologous repair (HR) and non-homologous end-joining repair (NHEJ) (4,5). Since choice of repair is strongly tied to damage sensing, these findings indicate that there may be an unreported role for p53 at the crossroads of initial damage sensing and downstream recruitment of and/or transcriptional 15 regulation of relevant repair factors.…”