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J. Biol. Chem., Vol. 283, Issue 41, 27514-27524, October 10, 2008

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Regulation of Telomere Length by Fatty Acid Elongase 3 in Yeast

INVOLVEMENT OF INOSITOL PHOSPHATE METABOLISM AND Ku70/80 FUNCTION^*

Suriyan Ponnusamy, Nathan L. Alderson, Hiroko Hama, Jacek Bielawski, James C. Jiang^¶, Rashna Bhandari^||, Solomon H. Snyder^||, S. Michal Jazwinski^¶, and Besim Ogretmen¹

From the Department of Biochemistry and Molecular Biology, and Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425, the ^¶Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70118, and the ^||Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

In this study, we investigated the roles of very long-chain fatty acid (VLCFA) synthesis by fatty acid elongase 3 (ELO3) in the regulation of telomere length and life span in the yeast Saccharomyces cerevisiae. Loss of VLCFA synthesis via deletion of ELO3 reduced telomere length, and reconstitution of the expression of wild type ELO3, and not by its mutant with decreased catalytic activity, rescued telomere attrition. Further experiments revealed that alterations of phytoceramide seem to be dispensable for telomere shortening in response to loss of ELO3. Interestingly, telomere shortening in elo3 cells was almost completely prevented by deletion of IPK2 or KCS1, which are involved in the generation of inositol phosphates (IP4, IP5, and inositol pyrophosphates). Deletion of IPK1, which generates IP6, however, did not affect regulation of telomere length. Further data also suggested that elo3 cells exhibit accelerated chronologic aging, and reduced replicative life span compared with wild type cells, and deletion of KCS1 helped recover these biological defects. Importantly, to determine downstream mechanisms, epistasis experiments were performed, and data indicated that ELO3 and YKU70/80 share a common pathway for the regulation of telomere length. More specifically, chromatin immunoprecipitation assays revealed that the telomere binding and protective function of YKu80p in vivo was reduced in elo3 cells, whereas its non-homologues end-joining function was not altered. Deletion of KCS1 in elo3 cells recovered the telomere binding and protective function of Ku, consistent with the role of KCS1 mutation in the rescue of telomere length attrition. Thus, these findings provide initial evidence of a possible link between Elo3-dependent VLCFA synthesis, and IP metabolism by KCS1 and IPK2 in the regulation of telomeres, which play important physiological roles in the control of senescence and aging, via a mechanism involving alterations of the telomere-binding/protection function of Ku.

Received for publication, April 17, 2008 , and in revised form, July 24, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants CA88932 and DE016572 (to B. O.) and AG006168 (to S. M. J.). 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 To whom correspondence should be addressed: 86 Jonathan Lucas St., Hollings Cancer Center, Rm. HO512A, Charleston, SC 29425. Tel.: 843-792-0940; Fax: 843-792-2556; E-mail: ogretmen{at}musc.edu.

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