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J. Biol. Chem., Vol. 282, Issue 28, 20395-20406, July 13, 2007

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PTIP Associates with MLL3- and MLL4-containing Histone H3 Lysine 4 Methyltransferase Complex^*

Young-Wook Cho, Teresa Hong¹, SunHwa Hong¹, Hong Guo, Hong Yu, Doyeob Kim^¶, Tad Guszczynski^||, Gregory R. Dressler^¶, Terry D. Copeland^||, Markus Kalkum, and Kai Ge²

From the Nuclear Receptor Biology Section, Clinical Endocrinology Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892, the Beckman Research Institute of the City of Hope, Immunology Division, Duarte, California 91010, the ^¶Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, and the ^||Laboratory of Protein Dynamics and Signaling, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702

PTIP, a protein with tandem BRCT domains, has been implicated in DNA damage response. However, its normal cellular functions remain unclear. Here we show that while ectopically expressed PTIP is capable of interacting with DNA damage response proteins including 53BP1, endogenous PTIP, and a novel protein PA1 are both components of a Set1-like histone methyltransferase (HMT) complex that also contains ASH2L, RBBP5, WDR5, hDPY-30, NCOA6, SET domain-containing HMTs MLL3 and MLL4, and substoichiometric amount of JmjC domain-containing putative histone demethylase UTX. PTIP complex carries robust HMT activity and specifically methylates lysine 4 (K4) on histone H3. Furthermore, PA1 binds PTIP directly and requires PTIP for interaction with the rest of the complex. Moreover, we show that hDPY-30 binds ASH2L directly. The evolutionarily conserved hDPY-30, ASH2L, RBBP5, and WDR5 likely constitute a subcomplex that is shared by all human Set1-like HMT complexes. In contrast, PTIP, PA1, and UTX specifically associate with the PTIP complex. Thus, in cells without DNA damage agent treatment, the endogenous PTIP associates with a Set1-like HMT complex of unique subunit composition. As histone H3 K4 methylation associates with active genes, our study suggests a potential role of PTIP in the regulation of gene expression.

Received for publication, February 22, 2007 , and in revised form, April 30, 2007.

Addendum—Issaeva et al. (Mol. Cell. Biol. (2007) 27, 1903) recently reported that the MLL4 (ALR) HMT complex contains PTIP.

^* This work was supported by the National Institutes of Health and by the Intramural Research Program of the NIDDK (to K. G.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Table S1.

This article was selected as a Paper of the Week.

¹ These authors contributed equally to this work.

² To whom correspondence should be addressed: Nuclear Receptor Biology Section, Clinical Endocrinology Branch, NIDDK, National Institutes of Health, Bethesda, MD 20892. Tel.: 301-451-1998; Fax: 301-480-1021; E-mail: kaig{at}niddk.nih.gov.

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