@article{171b4a0f34eb4ac0bad38e4d5fd10ad2,
title = "PHD Domain-Mediated E3 Ligase Activity Directs Intramolecular Sumoylation of an Adjacent Bromodomain Required for Gene Silencing",
abstract = "Tandem PHD and bromodomains are often found in chromatin-associated proteins and have been shown to cooperate in gene silencing. Each domain can bind specifically modified histones: the mechanisms of cooperation between these domains are unknown. We show that the PHD domain of the KAP1 corepressor functions as an intramolecular E3 ligase for sumoylation of the adjacent bromodomain. The RING finger-like structure of the PHD domain is required for both Ubc9 binding and sumoylation and directs modification to specific lysine residues in the bromodomain. Sumoylation is required for KAP1-mediated gene silencing and functions by directly recruiting the SETDB1 histone methyltransferase and the CHD3/Mi2 component of the NuRD complex via SUMO-interacting motifs. Sumoylated KAP1 stimulates the histone methyltransferase activity of SETDB1. These data provide a mechanistic explanation for the cooperation of PHD and bromodomains in gene regulation and describe a function of the PHD domain as an intramolecular E3 SUMO ligase.",
keywords = "DNA, PROTEINS",
author = "Ivanov, {Alexey V.} and Hongzhuang Peng and Vyacheslav Yurchenko and Yap, {Kyoko L.} and Negorev, {Dmitri G.} and Schultz, {David C.} and Elyse Psulkowski and Fredericks, {William J.} and White, {David E.} and Maul, {Gerd G.} and Sadofsky, {Moshe J.} and Zhou, {Ming Ming} and Rauscher, {Frank J.}",
note = "Funding Information: We thank Dr. S. Chiocca for pSG9-Gam1 and Dr. H. Saitoh for pTE1E2-S1/2 plasmids; Dr. R. Marmorstein and M. Holbert for purified mononucleosomes and core histones; Dr. E. Johnson for Smt3p antibody; and Lisa Gibson and Soumya Kandi for excellent technical assistance. F.J.R. is supported by National Institutes of Health (NIH) grants CA095561, CA092088, and DAMD17-02-1-0631, the Samuel Waxman Cancer Research Foundation, and The Emerald Foundation. M.-M.Z. is supported in part by NIH grant CA87658 and National Science Foundation grant #0517352. G.G.M. is supported by NIH grant AI41136 and GM57599. M.J.S. is supported by NIH grant AI41711, and V.Y. is supported by NIH grant CA09173. K.L.Y. is supported by a Terry Fox Foundation fellowship from the National Cancer Institute of Canada. D.E.W. is supported by NIH grant CA126283. We acknowledge the National Cancer Institute-Supported-Wistar Institute Cancer Center Shared Facilities: Genomics, Protein Expression, Proteomics and Hybridoma, and the Commonwealth Universal Research Enhancement Program, Pennsylvania Department of Health. ",
year = "2007",
month = dec,
day = "14",
doi = "10.1016/j.molcel.2007.11.012",
language = "English",
volume = "28",
pages = "823--837",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "5",
}