ARF triggers senescence in Brca2-deficient cells by altering the spectrum of p53 transcriptional targets

Carlos, A.R. and Escandell, J.M. and Kotsantis, P. and Suwaki, N. and Bouwman, P. and Badie, S. and Folio, C. and Benitez, J. and Gomez-Lopez, G. and Pisano, D.G. and Jonkers, J. and Tarsounas, M. (2013) ARF triggers senescence in Brca2-deficient cells by altering the spectrum of p53 transcriptional targets. Nature Communications, 4: 2697. ISSN 2041-1723

Full text not available from this repository.

Abstract

ARF is a tumour suppressor activated by oncogenic stress, which stabilizes p53. Although p53 is a key component of the response to DNA damage, a similar function for ARF has not been ascribed. Here we show that primary mouse and human cells lacking the tumour suppressor BRCA2 accumulate DNA damage, which triggers checkpoint signalling and ARF activation. Furthermore, senescence induced by Brca2 deletion in primary mouse and human cells is reversed by the loss of ARF, a phenotype recapitulated in cells lacking RAD51. Surprisingly, ARF is not necessary for p53 accumulation per se but for altering the spectrum of genes activated by this transcription factor. Specifically, ARF enables p53 transcription of Dusp4 and Dusp7, which encode a pair of phosphatases known to inactivate the MAP kinases ERK1/2. Our results ascribe a previously unanticipated function to the ARF tumour suppressor in genome integrity, controlled by replicative stress and ATM/ATR-dependent checkpoint responses.

Item Type:
Journal Article
Journal or Publication Title:
Nature Communications
Uncontrolled Keywords:
/dk/atira/pure/subjectarea/asjc/1300/1300
Subjects:
?? general biochemistry,genetics and molecular biologygeneral chemistrygeneral physics and astronomybiochemistry, genetics and molecular biology(all)chemistry(all)physics and astronomy(all) ??
ID Code:
200984
Deposited By:
Deposited On:
11 Aug 2023 15:25
Refereed?:
Yes
Published?:
Published
Last Modified:
16 Jul 2024 12:05