期刊名称:Proceedings of the National Academy of Sciences
印刷版ISSN:0027-8424
电子版ISSN:1091-6490
出版年度:2010
卷号:107
期号:12
页码:5511-5515
DOI:10.1073/pnas.1001223107
语种:English
出版社:The National Academy of Sciences of the United States of America
摘要:Rpa1, an essential gene involved in DNA replication and genome maintenance, is syntenic and linked to Trp53 in mice and humans. To study the genetic interaction between Rpa1 and Trp53 in tumorigenesis, we generated compound Rpa1L230P/+; Trp53+/- mutant mice with the mutant alleles in either trans or cis configuration. We demonstrate that the Rpa1L230P missense mutation significantly alters the tumor phenotype and spectrum of Trp53 mutant mice by modifying the genetic mechanisms underlying tumorigenesis. Importantly, when the Rpa1L230P and Trp53 mutant alleles are in cis, the tumor phenotype is attenuated and altered and loss of heterozygosity (LOH) at the Trp53 wild-type locus is selected against, whereas in the trans configuration, Rpa1L230P enhances the Trp53+/- tumor phenotype even though Rpa1L230P is ultimately lost by LOH. These studies indicate that polymorphic genetic variants in cell essential genes can genetically affect closely linked tumor suppressor loci via allelic phasing, which can result in profound phenotypic variations in tumorigenesis.
关键词:DNA repair ; genome instability ; loss of heterozygosity ; murine model ; tumor suppressor gene