ATM regulates a RASSF1A-dependent DNA damage response.
Hypermethylation of CpG islands in the RASSF1 promoter is one of the most frequent events identified in human cancer. The epigenetic-driven loss of RASSF1A protein expression is observed more often in tumors of higher grade and correlates with a decreased responsiveness to DNA-damaging therapy. Ras association domain-containing family 1A (RASSF1A) promotes apoptosis by signaling through the MST2 and LATS1 kinases, leading to stabilization of the YAP1/p73 transcriptional complex. Here we provide evidence for a new pathway linking DNA damage signaling to RASSF1A via the main sensor of double-strand breaks in cells, ataxia telangiectasia mutated (ATM). We show that, upon DNA damage, RASSF1A is phosphorylated by ATM on Ser131 and is involved in the activation of both MST2 and LATS1, leading to the stabilization of p73. Furthermore, lung and ovarian tumor cell lines that retain RASSF1A expression commonly harbor polymorphisms in the region of Ser131, and our analysis shows that the S131F polymorphism conveys resistance to DNA-damaging agents. Thus, we present a novel DNA damage pathway emanating from ATM that is frequently disabled in tumors via epigenetic silencing of RASSF1 or mutation of an ATM phosphorylation site.
Hamilton
Garth
G
Gray Institute for Radiation Oncology and Biology, University of Oxford, Old Road Campus Research Building, Roosevelt Drive, Oxford OX3 7DQ, UK.
Yee
Karen S
KS
Scrace
Simon
S
O'Neill
Eric
E
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D020868:Gene Silencing; D006801:Humans; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C411762:RASSF1 protein, human; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases