RPA-Mediated Recruitment of the E3 Ligase RFWD3 Is Vital for Interstrand Crosslink Repair and Human Health.
Mol Cell
; 66(5): 610-621.e4, 2017 Jun 01.
Article
em En
| MEDLINE
| ID: mdl-28575657
Defects in the repair of DNA interstrand crosslinks (ICLs) are associated with the genome instability syndrome Fanconi anemia (FA). Here we report that cells with mutations in RFWD3, an E3 ubiquitin ligase that interacts with and ubiquitylates replication protein A (RPA), show profound defects in ICL repair. An amino acid substitution in the WD40 repeats of RFWD3 (I639K) found in a new FA subtype abolishes interaction of RFWD3 with RPA, thereby preventing RFWD3 recruitment to sites of ICL-induced replication fork stalling. Moreover, single point mutations in the RPA32 subunit of RPA that abolish interaction with RFWD3 also inhibit ICL repair, demonstrating that RPA-mediated RFWD3 recruitment to stalled replication forks is important for ICL repair. We also report that unloading of RPA from sites of ICL induction is perturbed in RFWD3-deficient cells. These data reveal important roles for RFWD3 localization in protecting genome stability and preserving human health.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Dano ao DNA
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Origem de Replicação
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Ubiquitina-Proteína Ligases
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Proteína de Replicação A
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Anemia de Fanconi
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Reparo de DNA por Recombinação
Limite:
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article