UBC9 and EME1 sumoylation foster ribosomal DNA damage repair in CPT response

Abstract

UBC9 sumoylation (S*UBC9) in mammals contributes to SUMO target discrimination, biochemically1. Here, we present biological insights by characterizing a sumoylation mimetic UBC9-fusion (mCS~UBC9) in comparison to its wild-type (mCUBC9). We observe that sumoylation promotes UBC9s stability, nuclear localization and is beneficial for cell survival. We identified EME1, the regulatory subunit of the structure-specific endonuclease EME1-MUS81, as S*UBC9 substrate and demonstrate EME1 and UBC9 sumoylation being advantageous for survival upon Camptothecin (CPT) exposure. Moreover, mCS~UBC9 expression enhances double-strand breaks (DSBs) and replication upon CPT treatment, features assigned to the EME1-MUS81 complex2. EME1 and mCS~UBC9 co-localize in nucleolar repair-condensates, that enlarge and round when exposed to the drug. Together, these findings imply that S*UBC9-induced EME1 sumoylation improves ribosomal rDNA repair, which might prevent dangerous second template switches in highly repetitive ribosomal chromatin and allow the converging replication fork to complete DNA replication. Finally, we discuss implications of these findings for anti-cancer therapy.