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J. Biol. Chem., Vol. 280, Issue 6, 4264-4269, February 11, 2005
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¶**
From the
Departments of Pharmacology, Cancer Biology, and Biochemistry, Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710 and ||Department of Biology, University of North Carolina, Chapel Hill, North Carolina 27599-3280
Activation of phospholipase C-dependent inositol polyphosphate signaling pathways generates distinct messengers derived from inositol 1,4,5-trisphosphate that control gene expression and mRNA export. Here we report the regulation of telomere length by production of a diphosphorylinositol tetrakisphosphate, PP-IP4, synthesized by the KCS1 gene product. Loss of PP-IP4 production results in lengthening of telomeres, whereas overproduction leads to their shortening. This effect requires the presence of Tel1, the yeast homologue of ATM, the protein mutated in the human disease ataxia telangiectasia. Our data provide in vivo evidence of a regulatory link between inositol polyphosphate signaling and the checkpoint kinase family and describe a third nuclear process modulated by phospholipase C activation.
Received for publication, October 25, 2004 , and in revised form, November 18, 2004.
* This work was supported by funds from the Howard Hughes Medical Institute (to J. D. Y.) and from National Institutes of Health Grants HL-55672 (to J. D. Y.) and GM-531576 (to T. D. P.). 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.
Howard Hughes Medical Institute Physician Postdoctoral Fellow.
¶ Present address: Case Western Reserve University, Dept. of Biochemistry, School of Medicine, Wood Bldg., W464-B, 2109 Adelbert Rd., Cleveland, OH 44106.
** To whom correspondence should be addressed: Dept. of Pharmacology and Cancer Biology, Howard Hughes Medical Institute, Duke University Medical Center, DUMC 3813, Durham, NC 27710. Tel.: 919-681-6414; Fax: 919-668-0991; E-mail: yorkj{at}duke.edu.
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