MDC1 PST-repeat region promotes histone H2AX-independent chromatin association and DNA damage tolerance.
Nat Commun
; 10(1): 5191, 2019 11 15.
Article
em En
| MEDLINE
| ID: mdl-31729360
ABSTRACT
Histone H2AX and MDC1 are key DNA repair and DNA-damage signalling proteins. When DNA double-strand breaks (DSBs) occur, H2AX is phosphorylated and then recruits MDC1, which in turn serves as a docking platform to promote the localization of other factors, including 53BP1, to DSB sites. Here, by using CRISPR-Cas9 engineered human cell lines, we identify a hitherto unknown, H2AX-independent, function of MDC1 mediated by its PST-repeat region. We show that the PST-repeat region directly interacts with chromatin via the nucleosome acidic patch and mediates DNA damage-independent association of MDC1 with chromatin. We find that this region is largely functionally dispensable when the canonical γH2AX-MDC1 pathway is operative but becomes critical for 53BP1 recruitment to DNA-damage sites and cell survival following DSB induction when H2AX is not available. Consequently, our results suggest a role for MDC1 in activating the DDR in areas of the genome lacking or depleted of H2AX.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Dano ao DNA
/
Cromatina
/
Histonas
/
Proteínas de Ciclo Celular
/
Proteínas Adaptadoras de Transdução de Sinal
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Reino Unido