Cis lethal genetic interactions attenuate and alter p53 tumorigenesis

Yuxun Wang, Weijia Zhang, Lisa Edelmann, Richard D. Kolodner, Raju Kucherlapati, Winfried Edelmann

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)5511-5515
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume107
Issue number12
DOIs
StatePublished - Mar 23 2010

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Carcinogenesis
Loss of Heterozygosity
Essential Genes
Neoplasms
Alleles
Phenotype
Missense Mutation
DNA Replication
Maintenance
Genome

Keywords

  • DNA repair
  • Genome instability
  • Loss of heterozygosity
  • Murine model
  • Tumor suppressor gene

ASJC Scopus subject areas

  • General

Cite this

Cis lethal genetic interactions attenuate and alter p53 tumorigenesis. / Wang, Yuxun; Zhang, Weijia; Edelmann, Lisa; Kolodner, Richard D.; Kucherlapati, Raju; Edelmann, Winfried.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 107, No. 12, 23.03.2010, p. 5511-5515.

Research output: Contribution to journalArticle

Wang, Yuxun ; Zhang, Weijia ; Edelmann, Lisa ; Kolodner, Richard D. ; Kucherlapati, Raju ; Edelmann, Winfried. / Cis lethal genetic interactions attenuate and alter p53 tumorigenesis. In: Proceedings of the National Academy of Sciences of the United States of America. 2010 ; Vol. 107, No. 12. pp. 5511-5515.
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