PT - JOURNAL ARTICLE AU - Minxian Qian AU - Linyuan Peng AU - Zuojun Liu AU - Xiaolong Tang AU - Zimei Wang AU - Baohua Liu TI - SIRT6 as a transcriptional coactivator of GATA4 prevents doxorubicin cardiotoxicity independently of its deacylase activity AID - 10.1101/725044 DP - 2019 Jan 01 TA - bioRxiv PG - 725044 4099 - http://biorxiv.org/content/early/2019/08/05/725044.short 4100 - http://biorxiv.org/content/early/2019/08/05/725044.full AB - Activity dependent and independent functions for some enzymes are indispensable as significant biological regulators. Deacylase SIRT6 is well-known to improve stress resistance and promote lifespan extension through enzymatic activity-dependent gene silencing. However, whether and how SIRT6 non-enzymatically actives the transcriptional output hasn’t been characterized. Here, we revealed SIRT6 as a coactivator of GATA4, an essential transcription factor for postnatal cardiomyocyte survival, promoting the expression of anti-apoptotic gene. Chemotherapeutic drug, doxorubicin (DOX), remarkably and rapidly decreased SIRT6 expression, leading to transcriptional repression of GATA4 and cardiomyocyte apoptosis. Interestingly, SIRT6 interacted with GATA4 yet enhanced GATA4 acetylation independent of its deacylase activity, by recruiting the acetyltransferase Tip60 to form a trimeric complex. Nonacyl-mimetic mutation of GATA4 thoroughly blocked its ability against DOX cardiotoxicity. Moreover, Sirt6 transgenic mice exhibited preserved cardiac function with attenuated GATA4 activity in response to DOX. Thus, our studies uncover a previously unrecognized role of SIRT6 in cardioprotection independently of deacylase activity, providing the molecular basis to prevent chemotherapeutic side effects.