title: ARF triggers senescence in Brca2-deficient cells by altering the spectrum of p53 transcriptional targets.
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.
authors.affiliation: 1] Telomere and Genome Stability Group, The CR-UK/MRC Gray Institute for Radiation Oncology and Biology, Old Campus Road, Oxford OX3 7DQ, UK [2] [3].
authors.forename: Ana Rita
authors.initials: AR
authors.lastname: Carlos
authors.forename: Jose Miguel
authors.initials: JM
authors.lastname: Escandell
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Kotsantis
authors.forename: Natsuko
authors.initials: N
authors.lastname: Suwaki
authors.forename: Peter
authors.initials: P
authors.lastname: Bouwman
authors.forename: Sophie
authors.initials: S
authors.lastname: Badie
authors.forename: Cecilia
authors.initials: C
authors.lastname: Folio
authors.forename: Javier
authors.initials: J
authors.lastname: Benitez
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Gomez-Lopez
authors.forename: David G
authors.initials: DG
authors.lastname: Pisano
authors.forename: Jos
authors.initials: J
authors.lastname: Jonkers
authors.forename: Madalena
authors.initials: M
authors.lastname: Tarsounas
mesh_terms: D000818:Animals; D024682:BRCA2 Protein / Q000235:genetics*; D002460:Cell Line; D006224:Cricetinae; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D004249:DNA Damage; D044127:Epigenesis, Genetic; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D010641:Phenotype; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051135:Rad51 Recombinase / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C106711:BRCA2 protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D034741:RNA, Small Interfering; C495901:TP53 protein, human; D014157:Transcription Factors; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D048049:Extracellular Signal-Regulated MAP Kinases; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; C495154:Rad51 protein, mouse; D010744:Phosphoric Monoester Hydrolases