title: A RASSF1A polymorphism restricts p53/p73 activation and associates with poor survival and accelerated age of onset of soft tissue sarcoma.
abstract: RASSF1A (Ras association domain containing family 1A), a tumor suppressor gene that is frequently inactivated in human cancers, is phosphorylated by ataxia telangiectasia mutated (ATM) on Ser131 upon DNA damage, leading to activation of a p73-dependent apoptotic response. A single-nucleotide polymorphism located in the region of the key ATM activation site of RASSF1A predicts the conversion of alanine (encoded by the major G allele) to serine (encoded by the minor T allele) at residue 133 of RASSF1A (p.Ala133Ser). Secondary protein structure prediction studies suggest that an alpha helix containing the ATM recognition site is disrupted in the serine isoform of RASSF1A (RASSF1A-p.133Ser). In this study, we observed a reduced ability of ATM to recruit and phosphorylate RASSF1A-p.133Ser upon DNA damage. RASSF1A-p.133Ser failed to activate the MST2/LATS pathway, which is required for YAP/p73-mediated apoptosis, and negatively affected the activation of p53, culminating in a defective cellular response to DNA damage. Consistent with a defective p53 response, we found that male soft tissue sarcoma patients carrying the minor T allele encoding RASSF1A-p.133Ser exhibited poorer tumor-specific survival and earlier age of onset compared with patients homozygous for the major G allele. Our findings propose a model that suggests a certain subset of the population have inherently weaker p73/p53 activation due to inefficient signaling through RASSF1A, which affects both cancer incidence and survival.
authors.affiliation: Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, United Kingdom.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Yee
authors.forename: Lukasz
authors.initials: L
authors.lastname: Grochola
authors.forename: Garth
authors.initials: G
authors.lastname: Hamilton
authors.forename: Anna
authors.initials: A
authors.lastname: Grawenda
authors.forename: Elisabeth E
authors.initials: EE
authors.lastname: Bond
authors.forename: Helge
authors.initials: H
authors.lastname: Taubert
authors.forename: Peter
authors.initials: P
authors.lastname: Wurl
authors.forename: Gareth L
authors.initials: GL
authors.lastname: Bond
authors.forename: Eric
authors.initials: E
authors.lastname: O'Neill
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011989:Receptors, Thyrotropin / Q000235:genetics / Q000378:metabolism; D012509:Sarcoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D012983:Soft Tissue Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C411762:RASSF1 protein, human; D011989:Receptors, Thyrotropin; C495901:TP53 protein, human; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D020930:MAP Kinase Kinase Kinases; C093290:MAP3K10 protein, human; D002945:Cisplatin