Cis lethal genetic interactions attenuate and alter p53 tumorigenesis

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...

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Published in:Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 12; pp. 5511 - 5515
Main Authors: Wang, Yuxun, Zhang, Weijia, Edelmann, Lisa, Kolodner, Richard D, Kucherlapati, Raju, Edelmann, Winfried
Format: Journal Article
Language:English
Published: United States National Academy of Sciences 23-03-2010
National Acad Sciences
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Summary: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.
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Contributed by Richard D. Kolodner, February 2, 2010 (sent for review October 22, 2009)
1Present address: Department of Pharmaceutical and Biomedical Sciences, University of South Carolina, Columbia, SC 29208.
Author contributions: Y.W., R.D.K., and W.E. designed research; Y.W., W.Z., and L.E. performed research; Y.W., W.Z., L.E., R.D.K., R.K., and W.E. analyzed data; and Y.W., R.D.K., and W.E. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1001223107