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

Ana Rita Carlos, Jose Miguel Escandell, Panagiotis Kotsantis, Natsuko Suwaki, Peter Bouwman, Sophie Badie, Cecilia Folio, Javier Benitez, Gonzalo Gomez-Lopez, David G. Pisano, Jos Jonkers and Madalena Tarsounas ()
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Ana Rita Carlos: Telomere and Genome Stability Group, The CR-UK/MRC Gray Institute for Radiation Oncology and Biology
Jose Miguel Escandell: Telomere and Genome Stability Group, The CR-UK/MRC Gray Institute for Radiation Oncology and Biology
Panagiotis Kotsantis: Telomere and Genome Stability Group, The CR-UK/MRC Gray Institute for Radiation Oncology and Biology
Natsuko Suwaki: Telomere and Genome Stability Group, The CR-UK/MRC Gray Institute for Radiation Oncology and Biology
Peter Bouwman: The Netherlands Cancer Institute
Sophie Badie: Telomere and Genome Stability Group, The CR-UK/MRC Gray Institute for Radiation Oncology and Biology
Cecilia Folio: Telomere and Genome Stability Group, The CR-UK/MRC Gray Institute for Radiation Oncology and Biology
Javier Benitez: Human Cancer Genetics Program, Spanish National Cancer Center (CNIO)
Gonzalo Gomez-Lopez: Structural Biology and BioComputing Programme, Spanish National Cancer Center (CNIO)
David G. Pisano: Structural Biology and BioComputing Programme, Spanish National Cancer Center (CNIO)
Jos Jonkers: The Netherlands Cancer Institute
Madalena Tarsounas: Telomere and Genome Stability Group, The CR-UK/MRC Gray Institute for Radiation Oncology and Biology

Nature Communications, 2013, vol. 4, issue 1, 1-14

Abstract: 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.

Date: 2013
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DOI: 10.1038/ncomms3697

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