p53 gain-of-function cancer mutants induce genetic instability by inactivating ATM.
Tp53 is the most commonly mutated tumour-suppressor gene in human cancers. In addition to the loss of tumour-suppression function, some missense mutants gain novel oncogenic activities. To elucidate the nature of the gain of function, we introduced the most common p53 cancer mutations (R248W and R273H) independently into the humanized p53 knock-in (HUPKI) allele in mice. Tumour-suppressor functions of p53 are abolished in p53-mutant mice. Several lines of evidence further indicate gain-of-function of p53 mutants in promoting tumorigenesis. p53(R248W) mice rapidly succumb to certain types of cancers not commonly observed in p53(-/-) mice. Interchromosomal translocations, a type of genetic instability rarely observed in p53(-/-) cells, are readily detectable in p53-mutant pre-tumor thymocytes. Although normal in p53(-/-) mouse cells, the G(2)-M checkpoint is impaired in p53-mutant cells after DNA damage. These acquired oncogenic properties of mutant p53 could be explained by the findings that these p53 mutants interact with the nuclease Mre11 and suppress the binding of the Mre11-Rad50-NBS1 (MRN) complex to DNA double-stranded breaks (DSBs), leading to impaired Ataxia-telangiectasia mutated (ATM) activation. Therefore, p53 gain-of-function mutants promote tumorigenesis by a novel mechanism involving active disruption of critical DNA damage-response pathways.
Song
Hoseok
H
Division of Biological Sciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0322, USA.
Hollstein
Monica
M
Xu
Yang
Y
D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D017766:Acid Anhydride Hydrolases; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000235:genetics; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D045643:DNA Repair Enzymes / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic; D042822:Genomic Instability; D006657:Histones / Q000378:metabolism; D006801:Humans; D000076228:MRE11 Homologue Protein; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D013950:Thymus Gland / Q000166:cytology / Q000378:metabolism; D014158:Transcription, Genetic; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D014466:Ultraviolet Rays
D018528:ATP-Binding Cassette Transporters; D017766:Acid Anhydride Hydrolases; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D006657:Histones; D000076228:MRE11 Homologue Protein; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D051736:Proto-Oncogene Proteins c-mdm2; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C512689:Mre11a protein, mouse; C466108:Nijmegen breakage syndrome 1 protein, mouse; C495901:TP53 protein, human; C497207:Mdm2 protein, mouse; C576324:ATM protein, human; C576325:Atm protein, mouse; C495198:Rad50 protein, mouse; C475961:gamma-H2AX protein, mouse