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Cell cycle stage-specific roles of Rad18 in tolerance and repair of oxidative DNA damage.
Yang, Yang; Durando, Michael; Smith-Roe, Stephanie L; Sproul, Chris; Greenwalt, Alicia M; Kaufmann, William; Oh, Sehyun; Hendrickson, Eric A; Vaziri, Cyrus.
Afiliação
  • Yang Y; Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA. yangyang@email.unc.edu
Nucleic Acids Res ; 41(4): 2296-312, 2013 Feb 01.
Article em En | MEDLINE | ID: mdl-23295675
ABSTRACT
The E3 ubiquitin ligase Rad18 mediates tolerance of replication fork-stalling bulky DNA lesions, but whether Rad18 mediates tolerance of bulky DNA lesions acquired outside S-phase is unclear. Using synchronized cultures of primary human cells, we defined cell cycle stage-specific contributions of Rad18 to genome maintenance in response to ultraviolet C (UVC) and H(2)O(2)-induced DNA damage. UVC and H(2)O(2) treatments both induced Rad18-mediated proliferating cell nuclear antigen mono-ubiquitination during G(0), G(1) and S-phase. Rad18 was important for repressing H(2)O(2)-induced (but not ultraviolet-induced) double strand break (DSB) accumulation and ATM S1981 phosphorylation only during G(1), indicating a specific role for Rad18 in processing of oxidative DNA lesions outside S-phase. However, H(2)O(2)-induced DSB formation in Rad18-depleted G1 cells was not associated with increased genotoxin sensitivity, indicating that back-up DSB repair mechanisms compensate for Rad18 deficiency. Indeed, in DNA LigIV-deficient cells Rad18-depletion conferred H(2)O(2)-sensitivity, demonstrating functional redundancy between Rad18 and non-homologous end joining for tolerance of oxidative DNA damage acquired during G(1). In contrast with G(1)-synchronized cultures, S-phase cells were H(2)O(2)-sensitive following Rad18-depletion. We conclude that although Rad18 pathway activation by oxidative lesions is not restricted to S-phase, Rad18-mediated trans-lesion synthesis by Polη is dispensable for damage-tolerance in G(1) (because of back-up non-homologous end joining-mediated DSB repair), yet Rad18 is necessary for damage tolerance during S-phase.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ciclo Celular / Proteínas de Ligação a DNA / Reparo do DNA Limite: Humans Idioma: En Ano de publicação: 2013 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Ciclo Celular / Proteínas de Ligação a DNA / Reparo do DNA Limite: Humans Idioma: En Ano de publicação: 2013 Tipo de documento: Article