TY - JOUR
T1 - Cis lethal genetic interactions attenuate and alter p53 tumorigenesis
AU - Wang, Yuxun
AU - Zhang, Weijia
AU - Edelmann, Lisa
AU - Kolodner, Richard D.
AU - Kucherlapati, Raju
AU - Edelmann, Winfried
PY - 2010/3/23
Y1 - 2010/3/23
N2 - 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 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 Rpa1L230P and Trp53 mutant alleles are in cis, the tumor phenotypeis 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.
AB - 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 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 Rpa1L230P and Trp53 mutant alleles are in cis, the tumor phenotypeis 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.
KW - DNA repair
KW - Genome instability
KW - Loss of heterozygosity
KW - Murine model
KW - Tumor suppressor gene
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U2 - 10.1073/pnas.1001223107
DO - 10.1073/pnas.1001223107
M3 - Article
C2 - 20212136
AN - SCOPUS:77950411083
SN - 0027-8424
VL - 107
SP - 5511
EP - 5515
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 12
ER -