title: 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.
authors.affiliation: H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.
authors.forename: Lirong
authors.initials: L
authors.lastname: Peng
authors.forename: Hongbo
authors.initials: H
authors.lastname: Ling
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Yuan
authors.forename: Bin
authors.initials: B
authors.lastname: Fang
authors.forename: Gregory
authors.initials: G
authors.lastname: Bloom
authors.forename: Kenji
authors.initials: K
authors.lastname: Fukasawa
authors.forename: John
authors.initials: J
authors.lastname: Koomen
authors.forename: Jiandong
authors.initials: J
authors.lastname: Chen
authors.forename: William S
authors.initials: WS
authors.lastname: Lane
authors.forename: Edward
authors.initials: E
authors.lastname: Seto
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D057809:HEK293 Cells; D006367:HeLa Cells; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000074443:Lysine Acetyltransferase 5; D051379:Mice; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D013379:Substrate Specificity; D054875:Ubiquitination
chemical_list: D011994:Recombinant Proteins; D051548:Histone Acetyltransferases; C098489:KAT5 protein, human; C496552:KAT8 protein, human; D000074443:Lysine Acetyltransferase 5; C447939:SIRT1 protein, human; D056564:Sirtuin 1