PHD Domain-Mediated E3 Ligase Activity Directs Intramolecular Sumoylation of an Adjacent Bromodomain Required for Gene Silencing

Alexey V. Ivanov, Hongzhuang Peng, Vyacheslav Yurchenko, Kyoko L. Yap, Dmitri G. Negorev, David C. Schultz, Elyse Psulkowski, William J. Fredericks, David E. White, Gerd G. Maul, Moshe J. Sadofsky, Ming Ming Zhou, Frank J. Rauscher

Research output: Contribution to journalArticle

237 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)823-837
Number of pages15
JournalMolecular Cell
Volume28
Issue number5
DOIs
StatePublished - Dec 14 2007

    Fingerprint

Keywords

  • DNA
  • PROTEINS

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Ivanov, A. V., Peng, H., Yurchenko, V., Yap, K. L., Negorev, D. G., Schultz, D. C., Psulkowski, E., Fredericks, W. J., White, D. E., Maul, G. G., Sadofsky, M. J., Zhou, M. M., & Rauscher, F. J. (2007). PHD Domain-Mediated E3 Ligase Activity Directs Intramolecular Sumoylation of an Adjacent Bromodomain Required for Gene Silencing. Molecular Cell, 28(5), 823-837. https://doi.org/10.1016/j.molcel.2007.11.012