title: Mutation in Rpa1 results in defective DNA double-strand break repair, chromosomal instability and cancer in mice.
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 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.
authors.affiliation: Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
authors.forename: Yuxun
authors.initials: Y
authors.lastname: Wang
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Putnam
authors.forename: Michael F
authors.initials: MF
authors.lastname: Kane
authors.forename: Weijia
authors.initials: W
authors.lastname: Zhang
authors.forename: Lisa
authors.initials: L
authors.lastname: Edelmann
authors.forename: Robert
authors.initials: R
authors.lastname: Russell
authors.forename: Danaise V
authors.initials: DV
authors.lastname: Carrión
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: Raju
authors.initials: R
authors.lastname: Kucherlapati
authors.forename: Richard D
authors.initials: RD
authors.lastname: Kolodner
authors.forename: Winfried
authors.initials: W
authors.lastname: Edelmann
mesh_terms: D000782:Aneuploidy; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D043171:Chromosomal Instability / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020964:Embryo Loss / Q000235:genetics; D005260:Female; D006410:Hematopoiesis; D006579:Heterozygote; D006965:Hyperplasia; D007621:Karyotyping; D008221:Lymphoid Tissue / Q000473:pathology; D008223:Lymphoma / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D051716:Replication Protein A; D013997:Time Factors; D015003:Yeasts / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D051716:Replication Protein A; C497168:Rpa1 protein, mouse