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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Cis lethal genetic interactions attenuate and alter p53 tumorigenesis
Yuxun Wang1, Weijia Zhang, Lisa Edelmann
1Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. wangy@sccp.sc.edu
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.
Insights
Genetic variants in the essential Rpa1 gene impact tumor development in mice with Trp53 mutations. Allelic phasing influences tumor phenotype and progression, highlighting gene interactions in cancer.
Area of Science:
- Genetics
- Cancer Biology
- Genomics
Background:
- Rpa1 is crucial for DNA replication and genome maintenance.
- Rpa1 is syntenic (genetically linked) to Trp53, a key tumor suppressor gene, in mice and humans.
Purpose of the Study:
- To investigate the genetic interaction between Rpa1 and Trp53 in tumorigenesis.
- To determine how the Rpa1(L230P) mutation affects the tumor phenotype and spectrum of Trp53 mutant mice.
Main Methods:
- Generation of compound mutant mice: Rpa1(L230P/+); Trp53(+/-).
- Analysis of mutant alleles in cis (same chromosome) and trans (opposite chromosomes) configurations.
- Assessment of tumor phenotype, spectrum, and loss of heterozygosity (LOH) at the Trp53 locus.
Main Results:
- The Rpa1(L230P) mutation significantly alters the tumor phenotype and spectrum in Trp53 mutant mice.
- In cis configuration, the Rpa1(L230P) mutation attenuates the tumor phenotype, and LOH at the Trp53 wild-type locus is selected against.
- In trans configuration, Rpa1(L230P) enhances the Trp53(+/-) tumor phenotype, despite eventual LOH of Rpa1(L230P).
Conclusions:
- Polymorphic genetic variants in essential genes can influence linked tumor suppressor loci.
- Allelic phasing (cis vs. trans configuration) of interacting genes can lead to significant variations in tumorigenesis phenotypes.
- These findings reveal complex genetic interactions affecting cancer development and underscore the importance of considering gene linkage and allelic configuration.
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