Inactivation of a histone methyltransferase by mutations in human cancers.
Histone methyltransferase (HMT)(1) class enzymes that methylate lysine residues of histones or proteins contain a conserved catalytic core termed the SET domain, which shares sequence homology with an independently described sequence motif, the PR domain. Intact PR or SET sequence is required for tumor suppression functions, but it remains unclear whether it is histone methyltransferase activity that underlies tumor suppression. We now show that tumor suppressor RIZ1 (PRDM2) methylates histone H3 on lysine 9, and this activity is reduced by mutations in the PR domain found in human cancers. Also, S-adenosylhomocysteine or methyl donor deficiency inhibits RIZ1 and other H3 lysine 9 methylation activities. These results support the hypothesis that H3 lysine 9 methylation activities of a PR/SET domain have tumor suppression functions and may underlie carcinogenesis associated with dietary methyl donor deficiency.
Kim
Keun-Cheol
KC
Program in Cancer Genetics and Epigenetics, Cancer Research Center, The Burnham Institute, La Jolla, CA 92037, USA.
Geng
Liqing
L
Huang
Shi
S
D001859:Bone Neoplasms / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D004789:Enzyme Activation; D006367:HeLa Cells; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000378:metabolism; D006801:Humans; D008745:Methylation; D008780:Methyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics*; D012516:Osteosarcoma / Q000201:enzymology / Q000235:genetics; D011496:Protein Methyltransferases; D017434:Protein Structure, Tertiary; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics*
D004268:DNA-Binding Proteins; D006657:Histones; D009687:Nuclear Proteins; D014157:Transcription Factors; D000076983:Histone Methyltransferases; D008780:Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C093563:PRDM2 protein, human