Mutation in Rpa1 results in defective DNA double-strand break repair, chromosomal instability and cancer in mice.
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.
Wang
Yuxun
Y
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Putnam
Christopher D
CD
Kane
Michael F
MF
Zhang
Weijia
W
Edelmann
Lisa
L
Russell
Robert
R
Carrión
Danaise V
DV
Chin
Lynda
L
Kucherlapati
Raju
R
Kolodner
Richard D
RD
Edelmann
Winfried
W
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
D004268:DNA-Binding Proteins; D051716:Replication Protein A; C497168:Rpa1 protein, mouse