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J. Biol. Chem., Vol. 283, Issue 17, 11073-11077, April 25, 2008

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Direct Interaction between SET8 and Proliferating Cell Nuclear Antigen Couples H4-K20 Methylation with DNA Replication^*

Michael S. Y. Huen¹², Shirley M.-H. Sy¹³, Jan M. van Deursen, and Junjie Chen⁴

From the Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Connecticut 06520 and the Department of Pediatrics, Mayo Clinic College of Medicine, Rochester, Minnesota 55905

Chromatin endowed by histone modifications governs chromatin structure, which in turn represents a means to regulate cellular processes, including transcription and heterochromatin formation. Recent evidence revealed a plethora of enzymes that catalyze specific histone modifications for epigenetic maintenance, and dysregulation of which contributes to tumorigenesis and developmental defects. The histone methyltransferase SET8 (also known as Pr-Set7) was previously reported to monomethylate Lys²⁰ of histone H4. However, the temporal and spatial control of SET8 activity remains elusive. Here, we provide evidence to support that SET8 monomethylates Lys²⁰ of histone H4 during S phase by tethering to proliferating cell nuclear antigen via a putative proliferating cell nuclear antigen-interacting protein box. In addition, we show that SET8 function is required for S phase progression. Finally, deletion of SET8 in mice causes embryonic lethality, suggesting that SET8 plays an important role in mammalian embryogenesis.

Received for publication, December 28, 2007 , and in revised form, February 29, 2008.

^* This work was in part supported by National Institutes of Health Grant CA100109 (to J. C.). 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.

¹ Both authors contributed equally to this work.

² Supported by an Anna Fuller fellowship from the Yale Cancer Center.

³ Supported by the Croucher Foundation, Hong Kong.

⁴ Recipient of an Era of Hope Scholar award from the United States Department of Defense and a member of the Mayo Clinic Breast Specialized Program of Research Excellence (supported by NCI Grant P50 CA116201 from the National Institutes of Health). To whom correspondence should be addressed. Tel.: 203-785-3758; Fax: 203-785-7482; E-mail: junjie.chen{at}yale.edu.

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