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Molecular and Cellular Biology, June 2008, p. 3861-3872, Vol. 28, No. 11
0270-7306/08/$08.00+0     doi:10.1128/MCB.02050-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Synthetic Lethal Screens Identify Gene Silencing Processes in Yeast and Implicate the Acetylated Amino Terminus of Sir3 in Recognition of the Nucleosome Core{triangledown}

Tibor van Welsem,1 Floor Frederiks,1 Kitty F. Verzijlbergen,1 Alex W. Faber,1 Zara W. Nelson,3 David A. Egan,2 Daniel E. Gottschling,3 and Fred van Leeuwen1*

Division of Cellular Biochemistry,1 Molecular Screening Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands,2 Division of Basic Sciences, FHCRC, Seattle, Washington3

Received 14 November 2007/ Returned for modification 28 December 2007/ Accepted 19 March 2008

Dot1 methylates histone H3 lysine 79 (H3K79) on the nucleosome core and is involved in Sir protein-mediated silencing. Previous studies suggested that H3K79 methylation within euchromatin prevents nonspecific binding of the Sir proteins, which in turn facilitates binding of the Sir proteins in unmethylated silent chromatin. However, the mechanism by which the Sir protein binding is influenced by this modification is unclear. We performed genome-wide synthetic genetic array (SGA) analysis and identified interactions of DOT1 with SIR1 and POL32. The synthetic growth defects found by SGA analysis were attributed to the loss of mating type identity caused by a synthetic silencing defect. By using epistasis analysis, DOT1, SIR1, and POL32 could be placed in different pathways of silencing. Dot1 shared its silencing phenotypes with the NatA N-terminal acetyltransferase complex and the conserved N-terminal bromo adjacent homology (BAH) domain of Sir3 (a substrate of NatA). We classified all of these as affecting a common silencing process, and we show that mutations in this process lead to nonspecific binding of Sir3 to chromatin. Our results suggest that the BAH domain of Sir3 binds to histone H3K79 and that acetylation of the BAH domain is required for the binding specificity of Sir3 for nucleosomes unmethylated at H3K79.

* Corresponding author. Mailing address: The Netherlands Cancer Institute, Division of Cellular Biochemistry, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. Phone: 31-20-5121973. Fax: 31-20-5121989. E-mail: fred.v.leeuwen{at}nki.nl

{triangledown} Published ahead of print on 7 April 2008.

Molecular and Cellular Biology, June 2008, p. 3861-3872, Vol. 28, No. 11
0270-7306/08/$08.00+0     doi:10.1128/MCB.02050-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Sampath, V., Yuan, P., Wang, I. X., Prugar, E., van Leeuwen, F., Sternglanz, R. (2009). Mutational Analysis of the Sir3 BAH Domain Reveals Multiple Points of Interaction with Nucleosomes. Mol. Cell. Biol. 29: 2532-2545 [Abstract] [Full Text]  


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