The proteasome is involved in determining differential utilization of double-strand break repair pathways.
The DSS1 protein interacts with the breast cancer susceptibility protein BRCA2 that plays an integral role in the repair of DNA double-strand breaks (DSBs). DSS1 has also been shown to interact with components of the 26S proteasome in Saccharomyces cerevisiae and in human tumour cells. This raises the possibility of functional interplay between the DNA repair machinery and the proteasome. We show here that human DSS1 interacts with the RPN3 and RPN7 proteasome subunits and define regions of DSS1 important for the interactions with RPN3, RPN7 and BRCA2. We also show that BRCA2 interacts with RPN3 and RPN7 and that the BRCA2/RPN7 interaction is independent of DSS1. Finally, and most significantly, we demonstrate that the proteolytic activity of the proteasome is a determinant of the choice of DSB repair pathway; inhibition of proteasome proteolytic activity results in an increase in the utilization of potentially mutagenic single-strand annealing at the expense of a reduction in the level of error-free gene conversion. This confirms a functional link between DSB repair and proteasomal activity.
Gudmundsdottir
K
K
Gene Function Laboratory, The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London, UK.
Lord
C J
CJ
Ashworth
A
A
D051017:Apoptosis Regulatory Proteins; D024682:BRCA2 Protein / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics; D004249:DNA Damage; D004260:DNA Repair; D005095:Exoribonucleases; D005260:Female; D020022:Genetic Predisposition to Disease; D006602:Hexosyltransferases; D006801:Humans; D007700:Kinetics; D046988:Proteasome Endopeptidase Complex / Q000235:genetics* / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics
D051017:Apoptosis Regulatory Proteins; C118024:BLID protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C484606:SEM1 protein, human; D029701:Saccharomyces cerevisiae Proteins; D006602:Hexosyltransferases; C517590:RPN2 protein, human; D005095:Exoribonucleases; C098317:DSS1 protein, S cerevisiae; D046988:Proteasome Endopeptidase Complex