SIRT1 Negatively Regulates the Activities, Functions, and Protein Levels of hMOF and TIP60

Abstract

SIRT1 is a NAD⁺-dependent histone H4K16 deacetylase that controls several different normal physiologic and disease processes. Like most histone deacetylases, SIRT1 also deacetylates nonhistone proteins. Here, we show that two members of the MYST (MOZ, Ybf2/Sas3, Sas2, and TIP60) acetyltransferase family, hMOF and TIP60, are SIRT1 substrates. SIRT1 deacetylation of the enzymatic domains of hMOF and TIP60 inhibits their acetyltransferase activity and promotes ubiquitination-dependent degradation of these proteins. Importantly, immediately following DNA damage, the binding of SIRT1 to hMOF and TIP60 is transiently interrupted, with corresponding hMOF/TIP60 hyperacetylation. Lysine-to-arginine mutations in SIRT1-targeted lysines on hMOF and TIP60 repress DNA double-strand break repair and inhibit the ability of hMOF/TIP60 to induce apoptosis in response to DNA double-strand break. Together, these findings uncover novel pathways in which SIRT1 dynamically interacts with and regulates hMOF and TIP60 through deacetylation and provide additional mechanistic insights by which SIRT1 regulates DNA damage response.

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SUPPLEMENTAL MATERIAL

Supplemental material for this article may be found at http://dx.doi.org/10.1128/MCB.00496-12.

ACKNOWLEDGMENTS

We thank Tony Kouzarides for plasmids and John Neveu, Bogdan Budnik, Renee Robinson, Vicki Izumi, Umut Oguz, Xiaotao Qu, and the Moffitt Cancer Center Core Facility for their technical support. We are grateful to Xiang-Jiao Yang (McGill University), Yali Dou (University of Michigan), Jacques Cote (Centre hospitalier universitaire de Québec), and John Lucchesi (Emory University) for advice.

This work was supported by grants to E.S. from the NIH (R01GM081650) and the Kaul Foundation and by a fellowship to L.P. from the American Heart Association.