Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
Department of Radiation Oncology and Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA.
Cell Rep. 2021 Mar 30;34(13):108921. 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.
乳腺癌Ⅰ型易感蛋白（BRCA1）和 BRCA1 相关 RING 结构域蛋白 I（BARD1）异二聚体通过多种功能促进基因组完整性，包括同源重组（HR）的 DNA 双链断裂（DSB）修复。BRCA1-BARD1 异二聚体化是其相互稳定性、HR 功能和肿瘤抑制作用所必需的；然而，调控 BRCA1-BARD1 异二聚体化的上游信号事件尚不清楚。在这里，我们表明，SIRT2，一种去乙酰化酶和乳腺癌肿瘤抑制因子，通过去乙酰化促进 BRCA1-BARD1 异二聚体化。SIRT2 与 BRCA1-BARD1 复合物，并使 BARD1 RING 结构域中的保守赖氨酸去乙酰化，与 BRCA1 相互作用，促进 BRCA1-BARD1 异二聚体化，从而促进 BRCA1-BARD1 的稳定性、核保留和定位到 DNA 损伤部位，从而有助于有效进行 HR。我们的发现定义了通过 SIRT2 去乙酰化调控 BRCA1-BARD1 异二聚体化的机制，阐明了指导 BRCA1-BARD1 异二聚体化的关键上游信号事件，促进了 HR 和肿瘤抑制，并描绘了 SIRT2 在指导 HR 修复 DSB 中的作用。
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