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

Yuxun Wang, Christopher D. Putnam, Michael F. Kane, Weijia Zhang, Lisa Edelmann, Robert Russell, Danaise V. Carrión, Lynda Chin, Raju Kucherlapati, Richard D. Kolodner, Winfried Edelmann

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

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 semi-dominant 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.

Original languageEnglish (US)
Pages (from-to)750-755
Number of pages6
JournalNature Genetics
Volume37
Issue number7
DOIs
StatePublished - 2005

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Chromosomal Instability
Double-Stranded DNA Breaks
Mutation
Neoplasms
Chromosome Breakage
Comparative Genomic Hybridization
DNA
Aneuploidy
Fibroblasts
Yeasts
Maintenance

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Mutation in Rpa1 results in defective DNA double-strand break repair, chromosomal instability and cancer in mice. / Wang, Yuxun; Putnam, Christopher D.; Kane, Michael F.; Zhang, Weijia; Edelmann, Lisa; Russell, Robert; Carrión, Danaise V.; Chin, Lynda; Kucherlapati, Raju; Kolodner, Richard D.; Edelmann, Winfried.

In: Nature Genetics, Vol. 37, No. 7, 2005, p. 750-755.

Research output: Contribution to journalArticle

Wang, Y, Putnam, CD, Kane, MF, Zhang, W, Edelmann, L, Russell, R, Carrión, DV, Chin, L, Kucherlapati, R, Kolodner, RD & Edelmann, W 2005, 'Mutation in Rpa1 results in defective DNA double-strand break repair, chromosomal instability and cancer in mice', Nature Genetics, vol. 37, no. 7, pp. 750-755. https://doi.org/10.1038/ng1587
Wang, Yuxun ; Putnam, Christopher D. ; Kane, Michael F. ; Zhang, Weijia ; Edelmann, Lisa ; Russell, Robert ; Carrión, Danaise V. ; Chin, Lynda ; Kucherlapati, Raju ; Kolodner, Richard D. ; Edelmann, Winfried. / Mutation in Rpa1 results in defective DNA double-strand break repair, chromosomal instability and cancer in mice. In: Nature Genetics. 2005 ; Vol. 37, No. 7. pp. 750-755.
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