Inhibition of SUV39H1 methyltransferase activity by DBC1.
SUV39H1 is a histone H3K9-specific methyltransferase important for heterochromatin formation, regulation of gene expression, and induction of senescence in premalignant cells. SUV39H1 forms a complex with SirT1, and its activity is stimulated by SirT1 binding. Here we present evidence that the product of the DBC1 (deleted in breast cancer 1) gene disrupts the SUV39H1-SirT1 complex. Furthermore, DBC1 binds to the SUV39H1 catalytic domain and inhibits its ability to methylate histone H3 in vitro and in vivo. Knockdown of endogenous DBC1 increased the level of cellular H3K9 methylation. As expected, DBC1 also binds to SirT1 and inhibits the deacetylase activity of SirT1. These results identify DBC1 as a novel cellular inhibitor of SUV39H1 activity. DBC1 may be an important regulator of heterochromatin formation and genomic stability by disrupting the SUV39H1-SirT1 complex and inactivating both enzymes.
Li
Zhenyu
Z
Department of Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.
Chen
Lihong
L
Kabra
Neha
N
Wang
Chuangui
C
Fang
Jia
J
Chen
Jiandong
J
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D055785:Gene Knockdown Techniques; D006570:Heterochromatin / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D046912:Multiprotein Complexes / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C527450:CCAR2 protein, human; D006570:Heterochromatin; D046912:Multiprotein Complexes; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C407843:SUV39H1 protein, human; D008780:Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins