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J. Biol. Chem., Vol. 280, Issue 34, 30025-30031, August 26, 2005

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SET8 Recognizes the Sequence RHRK²⁰VLRDN within the N Terminus of Histone H4 and Mono-methylates Lysine 20^*

Yinliang Yin, Changdong Liu, Sau Na Tsai¶, Bo Zhou, Sai Ming Ngai¶||, and Guang Zhu**

From the Department of Biochemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, the ^¶Department of Biology, The Chinese University of Hong Kong, Shatin, Hong Kong, and the Department of Physics, The Eastern China Normal University, Shanghai 200062, China

Methylation of lysine 20 in histone H4 has been proven to play important roles in chromatin structure and gene regulation. SET8 is one of the methyltransferases identified to be specific for this modification. In this study, the minimal active SET domain of SET8 has been mapped to the region of amino acids 195–352. This region completely retains the same methylation activity and substrate specificity as the full-length SET8. The SET domain recognizes a stretch of specific amino acid sequence around lysine 20 of H4 for its methylation activity. Methylation assays with N terminus mutants of H4 that contain deletions and single alanine or glutamine substitutions of charged residues revealed that SET8 requires the sequence RHRK²⁰VLRDN for methylation at lysine 20. The individual mutation of any charged residue in this sequence to alanine or glutamine abolished or greatly decreased levels of methylation of lysine 20 of H4 by SET8. Interestingly, mutation of lysine 16 to alanine, arginine, glutamine, or methionine did not affect methylation of lysine 20 by the SET domain. Mass spectrometric analysis of synthesized H4 N-terminal peptides modified by SET8 showed that SET8 selectively mono-methylates lysine 20 of H4. Taken together, our results suggested that the coordination between the amino acid sequence RHRK²⁰VLRDN and the SET domain of SET8 determines the substrate specificity and multiplicity of methylation of lysine 20 of H4.

Received for publication, February 14, 2005 , and in revised form, June 13, 2005.

^* This work was supported by grants from the Research Grants Council of Hong Kong (Grant HKUST6139/03M) and High Impact Research Area grant from The Hong Kong University of Science and Technology. 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.

^|| Supported by an industrial fund from the GreaterChina Technology Group Ltd.

^** To whom correspondence should be addressed. Tel.: 852-2358-8705; Fax: 852-2358-1552; E-mail: gzhu{at}ust.hk.

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