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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.

Original publication

DOI

10.1158/0008-5472.CAN-11-2906

Type

Journal article

Journal

Cancer Res

Publication Date

01/05/2012

Volume

72

Pages

2206 - 2217

Keywords

Adolescent, Adult, Age of Onset, Aged, Aged, 80 and over, Alleles, Cell Line, Tumor, Cisplatin, DNA Damage, DNA Methylation, DNA-Binding Proteins, Female, Humans, MAP Kinase Kinase Kinases, Male, Middle Aged, Nuclear Proteins, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Receptors, Thyrotropin, Sarcoma, Signal Transduction, Soft Tissue Neoplasms, Tumor Protein p73, Tumor Suppressor Protein p53, Tumor Suppressor Proteins, Young Adult