Inositol diphosphate signaling regulates telomere length.
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.
York
Sally J
SJ
Departments of Pharmacology, Cancer Biology, and Biochemistry, Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina 27710, USA. yorkj@duke.edu
Armbruster
Blaine N
BN
Greenwell
Patricia
P
Petes
Thomas D
TD
York
John D
JD
D064007:Ataxia Telangiectasia Mutated Proteins; D001692:Biological Transport; D015139:Blotting, Southern; D018797:Cell Cycle Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D005816:Genetic Complementation Test; D006868:Hydrolysis; D007295:Inositol Phosphates / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation; D016366:Open Reading Frames; D010766:Phosphorylation; D017856:Phosphotransferases (Phosphate Group Acceptor); D010957:Plasmids / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D029701:Saccharomyces cerevisiae Proteins / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction; D016615:Telomere / Q000648:ultrastructure*; D013997:Time Factors; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D010738:Type C Phospholipases / Q000737:chemistry / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D007295:Inositol Phosphates; D012333:RNA, Messenger; D029701:Saccharomyces cerevisiae Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D017856:Phosphotransferases (Phosphate Group Acceptor); C098863:KCS1 protein, S cerevisiae; D010738:Type C Phospholipases