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Letter
Nature Genetics  37, 750 - 755 (2005)
Published online: 19 June 2005; | doi:10.1038/ng1587

Mutation in Rpa1 results in defective DNA double-strand break repair, chromosomal instability and cancer in mice

Yuxun Wang1, Christopher D Putnam2, Michael F Kane2, Weijia Zhang3, Lisa Edelmann4, Robert Russell5, Danaise V Carrión3, Lynda Chin6, Raju Kucherlapati3, Richard D Kolodner2 & Winfried Edelmann1

1  Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

2  Ludwig Institute for Cancer Research, Cancer Center and Departments of Medicine and Cellular and Molecular Medicine, University of California San Diego, La Jolla, California 92093, USA.

3  Harvard Medical School-Partners Healthcare Center for Genetics and Genomics, Harvard Medical School, Boston, Massachusetts 02115, USA.

4  Department of Human Genetics, Mount Sinai School of Medicine, New York University, New York, New York 10029, USA.

5  Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

6  Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

Correspondence should be addressed to Richard D Kolodner rkolodner@ucsd.edu or Winfried Edelmann edelmann@aecom.yu.edu
Most cancers have multiple chromosomal rearrangements; the molecular mechanisms that generate them remain largely unknown. Mice carrying a heterozygous missense change in one of the DNA-binding domains of Rpa1 develop lymphoid tumors, and their homozygous littermates succumb to early embryonic lethality. Array comparative genomic hybridization of the tumors identified large-scale chromosomal changes as well as segmental gains and losses. The Rpa1 mutation resulted in defects in DNA double-strand break repair and precipitated chromosomal breaks as well as aneuploidy in primary heterozygous mutant mouse embryonic fibroblasts. The equivalent mutation in yeast is hypomorphic and semidominant and enhanced the formation of gross chromosomal rearrangements in multiple genetic backgrounds. These results indicate that Rpa1 functions in DNA metabolism are essential for the maintenance of chromosomal stability and tumor suppression.


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Nature Genetics
ISSN: 1061-4036
EISSN: 1546-1718
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