The HDAC6-RNF168 axis regulates H2A/H2A.X ubiquitination to enable double-strand break repair.
Nucleic Acids Res
; 51(17): 9166-9182, 2023 09 22.
Article
em En
| MEDLINE
| ID: mdl-37503842
ABSTRACT
Histone deacetylase 6 (HDAC6) mediates DNA damage signaling by regulating the mismatch repair and nucleotide excision repair pathways. Whether HDAC6 also mediates DNA double-strand break (DSB) repair is unclear. Here, we report that HDAC6 negatively regulates DSB repair in an enzyme activity-independent manner. In unstressed cells, HDAC6 interacts with H2A/H2A.X to prevent its interaction with the E3 ligase RNF168. Upon sensing DSBs, RNF168 rapidly ubiquitinates HDAC6 at lysine 116, leading to HDAC6 proteasomal degradation and a restored interaction between RNF168 and H2A/H2A.X. H2A/H2A.X is ubiquitinated by RNF168, precipitating the recruitment of DSB repair factors (including 53BP1 and BRCA1) to chromatin and subsequent DNA repair. These findings reveal novel regulatory machinery based on an HDAC6-RNF168 axis that regulates the H2A/H2A.X ubiquitination status. Interfering with this axis might be leveraged to disrupt a key mechanism of cancer cell resistance to genotoxic damage and form a potential therapeutic strategy for cancer.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Reparo do DNA
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article