Regulation of telomere length by fatty acid elongase 3 in yeast. Involvement of inositol phosphate metabolism and Ku70/80 function.
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 elo3Delta 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 elo3Delta 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 elo3Delta cells, whereas its non-homologues end-joining function was not altered. Deletion of KCS1 in elo3Delta 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.
Ponnusamy
Suriyan
S
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425; Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425.
Alderson
Nathan L
NL
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425.
Hama
Hiroko
H
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425.
Bielawski
Jacek
J
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425; Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425.
Jiang
James C
JC
Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70118.
Bhandari
Rashna
R
Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Snyder
Solomon H
SH
Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205.
Jazwinski
S Michal
SM
Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70118.
Ogretmen
Besim
B
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina 29425; Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina 29425. Electronic address: ogretmen@musc.edu.
D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000096:biosynthesis* / Q000235:genetics; D017353:Gene Deletion; D007295:Inositol Phosphates / Q000235:genetics / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D017856:Phosphotransferases (Phosphate Group Acceptor) / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000201:enzymology* / Q000235:genetics; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D005227:Fatty Acids; D007295:Inositol Phosphates; D029701:Saccharomyces cerevisiae Proteins; C520769:YKU70 protein, S cerevisiae; C520770:YKU80 protein, S cerevisiae; D000123:Acetyltransferases; C107119:SUR4 protein, S cerevisiae; C425775:ARG82 protein, S cerevisiae; D017853:Phosphotransferases (Alcohol Group Acceptor); D017856:Phosphotransferases (Phosphate Group Acceptor); C098863:KCS1 protein, S cerevisiae