In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 12 ( 2010-03-23), p. 5511-5515
Abstract:
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 Rpa1 L230P/+ ; Trp53 +/− mutant mice with the mutant alleles in either trans or cis configuration. We demonstrate that the Rpa1 L230P missense mutation significantly alters the tumor phenotype and spectrum of Trp53 mutant mice by modifying the genetic mechanisms underlying tumorigenesis. Importantly, when the Rpa1 L230P 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, Rpa1 L230P enhances the Trp53 +/− tumor phenotype even though Rpa1 L230P 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.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1001223107
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2010
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
