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M513249200v1
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Papers In Press, published online ahead of print May 8, 2006
J. Biol. Chem, 10.1074/jbc.M513249200
Submitted on December 13, 2005
Accepted on May 8, 2006

The histone methyltransferase SETDB1 and the DNA methyltransferase DNMT3A interact directly and localize to promoters silenced in cancer cells

Hongwei Li, Tibor Rauch, Zhao-Xia Chen, Piroska E. Szabó, Arthur D. Riggs, and Gerd P. Pfeifer

Biology, City of Hope, Duarte, CA 91010

Corresponding Author: gpfeifer{at}coh.org

DNA CpG methylation can cooperate with histone H3 lysine 9 (H3-K9) methylation in heterochromatin formation and gene silencing. Trimethylation of H3-K9 by the recently identified euchromatic histone methyl-transferase SETDB1/ESET may be responsible for transcriptional repression of certain promoters. Here, we show that SETDB1 associates with endogenous DNA methyl-transferase activity. SETDB1 interacts with the de novo DNA methyltransferases DNMT3A and DNMT3B but not with the maintenance methyltransferase DNMT1. The interaction of SETDB1 with DNMT3A was further characterized and confirmed by in vivo and in vitro interaction studies. A direct interaction of the two proteins occurs through the N-terminus of SETDB1 and the PHD domain of DNMT3A. Co-expression of SETDB1 and DNMT3A was essential for repression of reporter gene expression in a Gal4-based tethering assay and resulted in their recruitment to the artificial promoter. We further demonstrate that the CpG-methylated promoters of the endogenous p53BP2 gene in HeLa cells and the RASSF1A gene in MDA-MB-231 cells are simultaneously occupied by both SETDB1 and DNMT3A proteins, which provides evidence for SETDB1 being at least partly responsible for H3-K9 trimethylation at the promoter of RASSF1A, a gene frequently silenced in human cancers. In summary, our data demonstrates the direct physical interaction and functional connection between the H3-K9 trimethylase SETDB1 and the DNA methyltransferase DNMT3A, and thus contributes to a better understanding of the complexity of the self-reinforcing hetero-chromatin machinery operating at silenced promoters.


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