USP39 promotes non-homologous end-joining repair by poly(ADP-ribose)-induced liquid demixing.
Nucleic Acids Res
; 49(19): 11083-11102, 2021 11 08.
Article
em En
| MEDLINE
| ID: mdl-34614178
ABSTRACT
Mutual crosstalk among poly(ADP-ribose) (PAR), activated PAR polymerase 1 (PARP1) metabolites, and DNA repair machinery has emerged as a key regulatory mechanism of the DNA damage response (DDR). However, there is no conclusive evidence of how PAR precisely controls DDR. Herein, six deubiquitinating enzymes (DUBs) associated with PAR-coupled DDR were identified, and the role of USP39, an inactive DUB involved in spliceosome assembly, was characterized. USP39 rapidly localizes to DNA lesions in a PAR-dependent manner, where it regulates non-homologous end-joining (NHEJ) via a tripartite RG motif located in the N-terminus comprising 46 amino acids (N46). Furthermore, USP39 acts as a molecular trigger for liquid demixing in a PAR-coupled N46-dependent manner, thereby directly interacting with the XRCC4/LIG4 complex during NHEJ. In parallel, the USP39-associated spliceosome complex controls homologous recombination repair in a PAR-independent manner. These findings provide mechanistic insights into how PAR chains precisely control DNA repair processes in the DDR.
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1
Base de dados:
MEDLINE
Assunto principal:
DNA
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Poli(ADP-Ribose) Polimerases
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Proteínas de Ligação a DNA
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Reparo do DNA por Junção de Extremidades
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Proteases Específicas de Ubiquitina
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DNA Ligase Dependente de ATP
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article