SIRT2 promotes BRCA1-BARD1 heterodimerization through deacetylation

• Published in: Cell reports (Cambridge) 2021-03, Vol.34 (13), p.108921-108921, Article 108921
• Main Authors: Minten, Elizabeth V., Kapoor-Vazirani, Priya, Li, Chunyang, Zhang, Hui, Balakrishnan, Kamakshi, Yu, David S.
• Format: Article
• Language: English
• Subjects: Acetylation; BRCA1; BRCA1 Protein - metabolism; Cell Nucleus - metabolism; DNA Damage; DNA damage response; DNA repair; HEK293 Cells; heterodimerization; Homologous Recombination; Humans; Protein Binding; Protein Domains; Protein Multimerization; Protein Stability; SIRT2; sirtuin; Sirtuin 2 - metabolism; stability; Tumor Suppressor Proteins - chemistry; Tumor Suppressor Proteins - metabolism; Ubiquitin-Protein Ligases - chemistry; Ubiquitin-Protein Ligases - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.108921

The breast cancer type I susceptibility protein (BRCA1) and BRCA1-associated RING domain protein I (BARD1) heterodimer promote genome integrity through pleiotropic functions, including DNA double-strand break (DSB) repair by homologous recombination (HR). BRCA1-BARD1 heterodimerization is required for their mutual stability, HR function, and role in tumor suppression; however, the upstream signaling events governing BRCA1-BARD1 heterodimerization are unclear. Here, we show that SIRT2, a sirtuin deacetylase and breast tumor suppressor, promotes BRCA1-BARD1 heterodimerization through deacetylation. SIRT2 complexes with BRCA1-BARD1 and deacetylates conserved lysines in the BARD1 RING domain, interfacing BRCA1, which promotes BRCA1-BARD1 heterodimerization and consequently BRCA1-BARD1 stability, nuclear retention, and localization to DNA damage sites, thus contributing to efficient HR. Our findings define a mechanism for regulation of BRCA1-BARD1 heterodimerization through SIRT2 deacetylation, elucidating a critical upstream signaling event directing BRCA1-BARD1 heterodimerization, which facilitates HR and tumor suppression, and delineating a role for SIRT2 in directing DSB repair by HR. [Display omitted] •The SIRT2 sirtuin deacetylase binds and deacetylates the BRCA1-BARD1 complex•BARD1 RING domain deacetylation by SIRT2 promotes BRCA1-BARD1 heterodimerization•SIRT2 promotes BRCA1-BARD1 stability, nuclear retention, and localization•BARD1 deacetylation by SIRT2 promotes homologous recombination repair Minten et al. show that SIRT2, a sirtuin deacetylase and tumor suppressor protein, promotes BRCA1-BARD1 heterodimerization through deacetylation of BARD1 at conserved lysines within its RING domain. These findings elucidate a critical upstream signaling event directing BRCA1-BARD1 heterodimerization, which facilitates HR and tumor suppression.