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Molecular and Cellular Biology, October 2007, p. 6832-6841, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.00745-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Simultaneous Mutation of Methylated Lysine Residues in Histone H3 Causes Enhanced Gene Silencing, Cell Cycle Defects, and Cell Lethality in Saccharomyces cerevisiae ^,

Yi Jin,¹ Amy M. Rodriguez,² Julie D. Stanton,² Ana A. Kitazono,³ and John J. Wyrick^1,2*

Molecular Plant Sciences,¹ School of Molecular Biosciences, Washington State University, Pullman, Washington 99164-4660,² Department of Biochemistry, Cellular and Molecular Biology, University of Tennessee, Knoxville, Tennessee 37996³

Received 27 April 2007/ Returned for modification 19 June 2007/ Accepted 21 July 2007

The methylation of specific lysine residues in histone H3 is integral to transcription regulation; however, little is known about how combinations of methylated lysine residues act in concert to regulate genome-wide transcription. We have systematically mutated methylated histone lysine residues in yeast and found that the triple mutation of H3K4, H3K36, and H3K79 to arginine (H3 K4,36,79R) is lethal. The histone H3 K4,36,79R mutant causes a mitotic cell cycle delay and a progressive transcription defect that initiates in telomere regions and then spreads into the chromosome. This effect is mediated by the silent information regulator (SIR) silencing complex, as we observe increased binding of the SIR complex to genomic regions adjacent to yeast telomeres in the H3 K4,36,79R mutant and deletion of SIR2, SIR3, or SIR4 rescues the lethal phenotype. Curiously, a yeast strain in which the histone methyltransferase genes are simultaneously deleted is viable. Indeed, deletion of the histone methyltransferase genes can suppress the H3 K4,36,79R lethal phenotype. These and other data suggest that the cause of lethality may in part be due to the association of histone methyltransferase enzymes with a histone substrate that cannot be methylated.

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* Corresponding author. Mailing address: Washington State University, School of Molecular Biosciences, Fulmer 675, Pullman, WA 99164-4660. Phone: (509) 335-8785. Fax: (509) 335-9688. E-mail: jwyrick{at}wsu.edu

Published ahead of print on 30 July 2007.

Supplemental material for this article may be found at http://mcb.asm.org/.

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Molecular and Cellular Biology, October 2007, p. 6832-6841, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.00745-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Chaudhuri, S., Wyrick, J. J., Smerdon, M. J. (2009). Histone H3 Lys79 methylation is required for efficient nucleotide excision repair in a silenced locus of Saccharomyces cerevisiae. Nucleic Acids Res 37: 1690-1700 [Abstract] [Full Text]  
• Jin, Y., Rodriguez, A. M., Wyrick, J. J. (2009). Genetic and Genomewide Analysis of Simultaneous Mutations in Acetylated and Methylated Lysine Residues in Histone H3 in Saccharomyces cerevisiae. Genetics 181: 461-472 [Abstract] [Full Text]