SIRT6 deacetylase activity improves stress resistance via gene silencing and genome maintenance. Here, we reveal a deacetylase-independent function of SIRT6, which promotes anti-apoptotic gene expression via the transcription factor GATA4. SIRT6 recruits TIP60 acetyltransferase to acetylate GATA4 at K328/330, thus enhancing its chromatin binding capacity. In turn, GATA4 inhibits the deacetylase activity of SIRT6, thus ensuring the local chromatin accessibility via TIP60-promoted H3K9 acetylation. Significantly, the treatment of doxorubicin (DOX), an anti-cancer chemotherapeutic, impairs the SIRT6-TIP60-GATA4 trimeric complex, blocking GATA4 acetylation and causing cardiomyocyte apoptosis. While GATA4 hyperacetylation-mimic retains the protective effect against DOX, the hypoacetylation-mimic loses such ability. Thus, the data reveal a novel SIRT6-TIP60-GATA4 axis, which promotes the anti-apoptotic pathway to prevent DOX toxicity. Targeting the trimeric complex constitutes a new strategy to improve the safety of DOX chemotherapy in clinical application.

中文翻译：

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SIRT6的脱乙酰基酶独立功能与GATA4转录因子和表观遗传激活相结合，可对抗心肌细胞凋亡。

SIRT6脱乙酰酶活性通过基因沉默和基因组维持提高了抗逆性。在这里，我们揭示了SIRT6的脱乙酰基酶独立功能，该功能通过转录因子GATA4促进抗凋亡基因的表达。SIRT6募集TIP60乙酰转移酶以在K328 / 330处乙酰化GATA4，从而增强其染色质结合能力。反过来，GATA4抑制SIRT6的脱乙酰基酶活性，从而通过TIP60促进的H3K9乙酰化确保局部染色质可及性。重要的是，抗癌化疗药物阿霉素（DOX）的治疗会损害SIRT6-TIP60-GATA4三聚体复合物，阻断GATA4乙酰化并导致心肌细胞凋亡。尽管GATA4超乙酰化模拟物保留了对DOX的保护作用，但低乙酰化模拟物却失去了这种能力。从而，数据揭示了新的SIRT6-TIP60-GATA4轴，该轴促进了抗凋亡途径以防止DOX毒性。靶向三聚体复合物构成了提高DOX化疗在临床应用中安全性的新策略。