Proteasome involvement in the repair of DNA double-strand breaks.
Affinity purification of the yeast 19S proteasome revealed the presence of Sem1 as a subunit. Its human homolog, DSS1, was found likewise to copurify with the human 19S proteasome. DSS1 is known to associate with the tumor suppressor protein BRCA2 involved in repair of DNA double-strand breaks (DSBs). We demonstrate that Sem1 is required for efficient repair of an HO-generated yeast DSB using both homologous recombination (HR) and nonhomologous end joining (NHEJ) pathways. Deletion of SEM1 or genes encoding other nonessential 19S or 20S proteasome subunits also results in synthetic growth defects and hypersensitivity to genotoxins when combined with mutations in well-established DNA DSB repair genes. Chromatin immunoprecipitation showed that Sem1 is recruited along with the 19S and 20S proteasomes to a DSB in vivo, and this recruitment is dependent on components of both the HR and NHEJ repair pathways, suggesting a direct role of the proteasome in DSB repair.
Krogan
Nevan J
NJ
Banting and Best Department of Medical Research, University of Toronto, 112 College Street, Toronto, Ontario M5G 1L6, Canada.
Lam
Mandy H Y
MH
Fillingham
Jeffrey
J
Keogh
Michael-Christopher
MC
Gebbia
Marinella
M
Li
Joyce
J
Datta
Nira
N
Cagney
Gerard
G
Buratowski
Stephen
S
Emili
Andrew
A
Greenblatt
Jack F
JF
D000251:Adenosine Triphosphatases / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology; D004260:DNA Repair / Q000502:physiology*; D010450:Endopeptidases / Q000378:metabolism; D005095:Exoribonucleases; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*
C117424:SEM1 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D005095:Exoribonucleases; C098317:DSS1 protein, S cerevisiae; D010450:Endopeptidases; D046988:Proteasome Endopeptidase Complex; C119011:26S proteasome non-ATPase regulatory subunit 13; D000251:Adenosine Triphosphatases