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Cellular and Molecular Biology 18: DNA Repair and Genomic Instability

A missense mutation in replication protein A1 acts as a genetic modifier of p53 tumorigenesis

Yuxun Wang, Michael Kane, Steven Brunnert, Raju Kucherlapati, Richard D. Kolodner and Winfried Edelmann
Yuxun Wang
Albert Einstein College of Medicine, Department of Cell Biology, Bronx, NY, Ludwig Institute for Cancer Research, LaJolla, CA, Histotechnology and Comparative Pathology Facility, Albert Einstein College of Medicine, NY, Harvard Medical School-Partners Healthcare Center for Genetics and Genomics, Boston, MA, Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY
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Michael Kane
Albert Einstein College of Medicine, Department of Cell Biology, Bronx, NY, Ludwig Institute for Cancer Research, LaJolla, CA, Histotechnology and Comparative Pathology Facility, Albert Einstein College of Medicine, NY, Harvard Medical School-Partners Healthcare Center for Genetics and Genomics, Boston, MA, Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY
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Steven Brunnert
Albert Einstein College of Medicine, Department of Cell Biology, Bronx, NY, Ludwig Institute for Cancer Research, LaJolla, CA, Histotechnology and Comparative Pathology Facility, Albert Einstein College of Medicine, NY, Harvard Medical School-Partners Healthcare Center for Genetics and Genomics, Boston, MA, Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY
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Raju Kucherlapati
Albert Einstein College of Medicine, Department of Cell Biology, Bronx, NY, Ludwig Institute for Cancer Research, LaJolla, CA, Histotechnology and Comparative Pathology Facility, Albert Einstein College of Medicine, NY, Harvard Medical School-Partners Healthcare Center for Genetics and Genomics, Boston, MA, Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY
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Richard D. Kolodner
Albert Einstein College of Medicine, Department of Cell Biology, Bronx, NY, Ludwig Institute for Cancer Research, LaJolla, CA, Histotechnology and Comparative Pathology Facility, Albert Einstein College of Medicine, NY, Harvard Medical School-Partners Healthcare Center for Genetics and Genomics, Boston, MA, Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY
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Winfried Edelmann
Albert Einstein College of Medicine, Department of Cell Biology, Bronx, NY, Ludwig Institute for Cancer Research, LaJolla, CA, Histotechnology and Comparative Pathology Facility, Albert Einstein College of Medicine, NY, Harvard Medical School-Partners Healthcare Center for Genetics and Genomics, Boston, MA, Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY
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DOI:  Published May 2005
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Proc Amer Assoc Cancer Res, Volume 46, 2005

Abstract

1628

Previously we demonstrated that homozygosity of a single missense mutation in replication protein A1 (Rpa1L230P) resulted in cell lethality, whereas heterozygosity for this mutation caused defective DNA double-strand break repair, chromosomal instability and increased spontaneous tumorigenesis. Rpa1 was shown to physically interact with the tumor suppressor p53 in mammalian cells. Moreover, Rpa1 is syntenic and in close proximity to p53 in mice and humans and both gene loci have been implicated in human cancers. To study the genetic interaction between Rpa1 and p53 in tumorigenesis, we have generated compound Rpa1+/m; p53+/− mutant mice with the mutant alleles either in trans- or cis-configuration as well as Rpa1+/m; p53-/- mice. Both loss of heterozygosity (LOH) and haploinsufficiency have been proposed as possible mechanisms for tumorigenesis in p53+/− mice. We demonstrate that the Rpa1 missense mutation significantly alters the tumor phenotypes of p53 mutant mice by modifying the genetic mechanisms underlying tumor formation in the compound mutant mice including LOH at the wild-type p53 locus. These studies indicate that polymorphic genetic variants in essential genes can genetically affect closely linked disease-associated loci via allelic phasing which can result in profound phenotypic variations in tumorigenesis.

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Cancer Research: 65 (9 Supplement)
May 2005
Volume 65, Issue 9 Supplement
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A missense mutation in replication protein A1 acts as a genetic modifier of p53 tumorigenesis
Yuxun Wang, Michael Kane, Steven Brunnert, Raju Kucherlapati, Richard D. Kolodner and Winfried Edelmann
Cancer Res May 1 2005 (65) (9 Supplement) 382-383;

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A missense mutation in replication protein A1 acts as a genetic modifier of p53 tumorigenesis
Yuxun Wang, Michael Kane, Steven Brunnert, Raju Kucherlapati, Richard D. Kolodner and Winfried Edelmann
Cancer Res May 1 2005 (65) (9 Supplement) 382-383;
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Cancer Research Online ISSN: 1538-7445
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