PARP1-driven repair of topoisomerase IIIα DNA-protein crosslinks by FEN1.
Cell Rep
; 43(8): 114522, 2024 Aug 27.
Article
em En
| MEDLINE
| ID: mdl-39028621
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 and that inhibiting the ubiquitin-activating enzyme E1 (UBE1) increases TOP3A-DPCs, consistent with ubiquitylation serving as a signaling mechanism for TOP3A-DPC repair mediated by SPRTN and TDP2. We propose that two concerted pathways repair TOP3A-DPCs PARylation-driven FEN1 excision and ubiquitylation-driven SPRTN-TDP2 excision.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
DNA Topoisomerases Tipo I
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Endonucleases Flap
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Reparo do DNA
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Ubiquitinação
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Poli(ADP-Ribose) Polimerase-1
Limite:
Humans
Idioma:
En
Revista:
Cell Rep
Ano de publicação:
2024
Tipo de documento:
Article