HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

J. Biol. Chem., Vol. 282, Issue 52, 37805-37814, December 28, 2007

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 282/52/37805    most recent M706384200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Thaminy, S. Articles by Bedalov, A. Search for Related Content PubMed PubMed Citation Articles by Thaminy, S. Articles by Bedalov, A. Social Bookmarking                      What's this?

Hst3 Is Regulated by Mec1-dependent Proteolysis and Controls the S Phase Checkpoint and Sister Chromatid Cohesion by Deacetylating Histone H3 at Lysine 56^*

Safia Thaminy¹, Benjamin Newcomb¹, Jessica Kim, Tonibelle Gatbonton, Eric Foss, Julian Simon, and Antonio Bedalov^¶2

From the Clinical Research Division and Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109 and the ^¶Department of Medicine, University of Washington, Seattle, Washington 98109

The SIR2 homologues HST3 and HST4 have been implicated in maintenance of genome integrity in the yeast Saccharomyces cerevisiae. We find that Hst3 has NAD-dependent histone deacetylase activity in vitro and that it functions during S phase to deacetylate the core domain of histone H3 at lysine 56 (H3K56). In response to genotoxic stress, Hst3 undergoes rapid Mec1-dependent phosphorylation and is targeted for ubiquitin-mediated proteolysis, thus providing a mechanism for the previously observed checkpoint-dependent accumulation of Ac-H3K56 at sites of DNA damage. Loss of Hst3-mediated regulation of H3K56 acetylation results in a defect in the S phase DNA damage checkpoint. The pathway that regulates H3K56 acetylation acts in parallel with the Rad9 pathway to transmit a DNA damage signal from Mec1 to Rad53. We also observe that loss of Hst3 function impairs sister chromatid cohesion (SCC). Both S phase checkpoint and SCC defects are phenocopied by H3K56 point mutants. Our findings demonstrate that Hst3-regulated H3K56 acetylation safeguards genome stability by controlling the S phase DNA damage response and promoting SCC.

Received for publication, August 2, 2007 , and in revised form, October 3, 2007.

^* This work was supported by National Institutes of Health Grants HL04211 and DK56465, Doctors Cancer Foundation, and the Leukemia and Lymphoma Society. 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 1 and Figs. 7-9.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: Fred Hutchinson Cancer Research Center, 1100 Fairview Ave. N., Seattle, WA 98109. Tel.: 206-667-48-63; Fax: 206-667-56-69; E-mail: abedalov{at}fhcrc.org.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				B. Yang, A. Miller, and A. L. Kirchmaier HST3/HST4-dependent Deacetylation of Lysine 56 of Histone H3 in Silent Chromatin Mol. Biol. Cell, November 1, 2008; 19(11): 4993 - 5005. [Abstract] [Full Text] [PDF]

				I. Celic, A. Verreault, and J. D. Boeke Histone H3 K56 Hyperacetylation Perturbs Replisomes and Causes DNA Damage Genetics, August 1, 2008; 179(4): 1769 - 1784. [Abstract] [Full Text] [PDF]

				A. Miller, B. Yang, T. Foster, and A. L. Kirchmaier Proliferating Cell Nuclear Antigen and ASF1 Modulate Silent Chromatin in Saccharomyces cerevisiae via Lysine 56 on Histone H3 Genetics, June 1, 2008; 179(2): 793 - 809. [Abstract] [Full Text] [PDF]