Cellular stressors are known to inhibit the p53–RPA70 (replication protein A, 70 kDa subunit) complex, and RPA70 increases cellular DNA repair in cancer cells. We hypothesized that regulation of RPA70-mediated DNA repair might be responsible for the inhibition of apoptosis in hypoxic tumours. We have shown that, in cancer cells, hypoxia disrupts the p53–RPA70 complex, thereby enhancing RPA70-mediated NER (nucleotide excision repair)/NHEJ (non-homologous end-joining) repair. In normal cells, RPA70 binds to the p53-NTD (N-terminal domain), whereas this binding is disrupted in hypoxia. Phosphorylation of p53-NTD is a crucial event in dissociating both NTD–RPA70 and p53–RPA70 complexes. Serial mutations at serine and threonine residues in the NTD confirm that p53Ser15 phosphorylation induces dissociation of the p53–RPA70 complex in hypoxia. DNA-PK (DNA-dependent protein kinase) is shown to induce p53Ser15 phosphorylation, thus enhancing RPA70-mediated NER/NHEJ repair. Furthermore, RPA70 gene silencing induces significant increases in cellular apoptosis in the resistant hypoxic cancer cells. We have thus elucidated a novel pathway showing how DNA-PK-mediated p53Ser15 phosphorylation dissociates the p53–RPA70 complex, thus enhancing NER/NHEJ repair, which causes resistance to apoptosis in hypoxic cancer cells. This novel finding may open new strategies in developing cancer therapeutics on the basis of the regulation of RPA70-mediated NER/NHEJ repair.
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Research Article|
April 16 2012
p53 Ser15 phosphorylation disrupts the p53–RPA70 complex and induces RPA70-mediated DNA repair in hypoxia
Esha Madan;
Esha Madan
1
1Transcription and Human Biology Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India
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Rajan Gogna;
Rajan Gogna
1
1Transcription and Human Biology Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India
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Uttam Pati
Uttam Pati
2
1Transcription and Human Biology Laboratory, School of Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India
2To whom correspondence should be addressed (email uttam@mail.jnu.ac.in).
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Publisher: Portland Press Ltd
Received:
September 08 2011
Revision Received:
January 03 2012
Accepted:
January 30 2012
Accepted Manuscript online:
January 30 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 443 (3): 811–820.
Article history
Received:
September 08 2011
Revision Received:
January 03 2012
Accepted:
January 30 2012
Accepted Manuscript online:
January 30 2012
Citation
Esha Madan, Rajan Gogna, Uttam Pati; p53 Ser15 phosphorylation disrupts the p53–RPA70 complex and induces RPA70-mediated DNA repair in hypoxia. Biochem J 1 May 2012; 443 (3): 811–820. doi: https://doi.org/10.1042/BJ20111627
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