SIRT2 promotes BRCA1-BARD1 heterodimerization through deacetylation.
SIRT2 promotes BRCA1-BARD1 heterodimerization through deacetylation.
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DOI：
10.1016/j.celrep.2021.108921
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发表时间：
2021-03-30
期刊：
影响因子：
8.8
通讯作者：
Yu DS
中科院分区：
文献类型：
--
作者：
Minten EV;Kapoor-Vazirani P;Li C;Zhang H;Balakrishnan K;Yu DS
乳腺癌I型易感蛋白（BRCA 1）和BRCA 1相关RING结构域蛋白I（BARD 1）异二聚体通过多效性功能促进基因组完整性，包括通过同源重组（HR）修复DNA双链断裂（DSB）。BRCA 1-BARD 1异源二聚化是其相互稳定性、HR功能和肿瘤抑制作用所必需的;然而，控制BRCA 1-BARD 1异源二聚化的上游信号事件尚不清楚。在这里，我们表明SIRT 2，沉默调节蛋白脱乙酰酶和乳腺癌抑制因子，促进BRCA 1-BARD 1异源二聚体通过脱乙酰化。SIRT 2与BRCA 1-BARD 1复合并使BARD 1 RING结构域中的保守赖氨酸脱乙酰化，与BRCA 1介导，其促进BRCA 1-BARD 1异源二聚化并因此促进BRCA 1-BARD 1稳定性、核保留和定位于DNA损伤位点，从而有助于有效的HR。我们的研究结果定义了通过SIRT 2脱乙酰化调节BRCA 1-BARD 1异源二聚化的机制，阐明了指导BRCA 1-BARD 1异源二聚化的关键上游信号事件，其促进HR和肿瘤抑制，并描述了SIRT 2在通过HR指导DSB修复中的作用。Minten等表明SIRT 2，一种沉默调节蛋白脱乙酰酶和肿瘤抑制蛋白，通过BARD 1在其RING结构域内保守赖氨酸的脱乙酰化促进BRCA 1-BARD 1异源二聚化。这些发现阐明了指导BRCA 1-BARD 1异源二聚化的关键上游信号传导事件，其促进HR和肿瘤抑制。
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. 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.
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DOI：
10.1083/jcb.201110008
发表时间：
2012-04-16
期刊：
The Journal of cell biology
影响因子：
--
作者：
Kawai S;Amano A
通讯作者：
Amano A
影响因子：
16
作者：
Hatchi, Elodie;Skourti-Stathaki, Konstantina;Ventz, Steffen;Pinello, Luca;Yen, Angela;Kamieniarz-Gdula, Kinga;Dimitrov, Stoil;Pathania, Shailja;McKinney, Kristine M.;Eaton, Matthew L.;Kellis, Manolis;Hill, Sarah J.;Parmigiani, Giovanni;Proudfoot, Nicholas J.;Livingston, David M.
通讯作者：
Livingston, David M.
影响因子：
4.8
作者：
Hashizume, R;Fukuda, M;Ohta, T
通讯作者：
Ohta, T
影响因子：
30.8
作者：
FRIEDMAN, LS;OSTERMEYER, EA;KING, MC
通讯作者：
KING, MC
影响因子：
56.9
作者：
Kleiman, FE;Manley, JL
通讯作者：
Manley, JL