title: hMOF acetylation of DBC1/CCAR2 prevents binding and inhibition of SirT1.
abstract: The NAD(+)-dependent deacetylase SirT1 regulates gene silencing and genomic stability in response to nutrient deprivation and DNA damage. An important regulator of SirT1 in mammalian cells is DBC1 (deleted in breast cancer 1; KIAA1967 or CCAR2), which binds to SirT1 and inhibits the deacetylation of substrates. Recent studies have revealed that ATM/ATR-mediated phosphorylation of DBC1 promotes binding to SirT1. Here we show that DBC1 is modified by acetylation on two N-terminal lysine residues (K112 and K215). The MYST family histone acetyltransferase hMOF (human MOF) is responsible for DBC1 acetylation. Acetylation of K112 and K215 inhibits DBC1-SirT1 binding and increases SirT1 deacetylase activity. SirT1 also promotes DBC1 deacetylation, suggesting the presence of a negative-feedback mechanism that stabilizes the SirT1-DBC1 complex and limits SirT1 activity. hMOF binding and acetylation of DBC1 are inhibited after DNA damage in an ATM-dependent fashion, contributing to increased SirT1-DBC1 binding after DNA damage. Furthermore, a DBC1 mutant that mimics the acetylated state fails to promote apoptosis after DNA damage. These results suggest that acetylation of DBC1 inhibits binding to SirT1 and serves as a mechanism that connects DNA damage signaling to SirT1 and cell fate determination.
authors.affiliation: Molecular Oncology Department, Moffitt Cancer Center, Tampa, Florida, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Zheng
authors.forename: Leixiang
authors.initials: L
authors.lastname: Yang
authors.forename: Lirong
authors.initials: L
authors.lastname: Peng
authors.forename: Victoria
authors.initials: V
authors.lastname: Izumi
authors.forename: John
authors.initials: J
authors.lastname: Koomen
authors.forename: Edward
authors.initials: E
authors.lastname: Seto
authors.forename: Jiandong
authors.initials: J
authors.lastname: Chen
mesh_terms: D000107:Acetylation; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D004249:DNA Damage; D055785:Gene Knockdown Techniques; D051548:Histone Acetyltransferases / Q000378:metabolism*; D006801:Humans; D011485:Protein Binding; D025941:Protein Interaction Mapping; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000235:genetics; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C527450:CCAR2 protein, human; D034741:RNA, Small Interfering; D051548:Histone Acetyltransferases; C496552:KAT8 protein, human; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C447939:SIRT1 protein, human; D056564:Sirtuin 1