PARP1-driven repair of topoisomerase IIIα DNA-protein crosslinks by FEN1.

ABSTRACT: Persistent DNA-protein crosslinks formed by human topoisomerase IIIα (TOP3A-DPCs) interfere with DNA metabolism and lead to genome damage and cell death. Recently, we demonstrated that such abortive TOP3A-DPCs are ubiquitylated and proteolyzed by Spartan (SPRTN). Here, we identify transient poly(ADP-ribosylation) (PARylation) in addition to ubiquitylation as a signaling mechanism for TOP3A-DPC repair and provide evidence that poly(ADP-ribose) polymerase 1 (PARP1) drives the repair of TOP3A-DPCs by recruiting flap endonuclease 1 (FEN1) to the TOP3A-DPCs. We find that blocking PARylation attenuates the interaction of FEN1 and TOP3A and that TOP3A-DPCs accumulate in cells with compromised PARP1 activity and in FEN1-deficient cells. We also show that PARP1 suppresses TOP3A-DPC ubiquitylation a

SUBMITTER: Saha LK 

PROVIDER: S-EPMC11513513 | biostudies-literature | 2024 Aug

REPOSITORIES: biostudies-literature