title: The catalytic subunit of human telomerase is a unique caspase-6 and caspase-7 substrate.
abstract: Telomerase is a ribonucleoprotein complex that is essential for persistent cellular proliferation. The catalytic subunit of human telomerase, hTERT, functions as a reverse transcriptase and promotes vitality by maintaining telomeric DNA length. hTERT is tightly regulated with complex but poorly understood positive and negative regulation at several levels including transcription, protein-protein interactions, and post-translation modifications. Because evidence implicates hTERT as an apoptosis inhibitor and because telomerase activity tends to decrease during apoptosis, we hypothesized that hTERT is a caspase substrate leading to down regulation during apoptosis. Caspases are proteases that initiate and execute apoptosis by cleaving target proteins. Indeed, we found that caspases-6 and -7 cleave hTERT during apoptosis in cultured cells. Caspase-6 cleaves at residues D129 and D637, and caspase-7 cleaves at E286 and D628. Three of the caspase cleavage sites are unique motifs. All four caspase motifs appear conserved in TERTs from Old World monkeys and apes, and the caspase-6 sites appear conserved in all primates. The caspase site that cleaves at D129 appears conserved in amniotes. hTERT fragments generated by cleavage were remarkably persistent, lasting hours after caspase activation. These results reveal a new biologically relevant mechanism for telomerase down regulation through caspase-mediated cleavage of hTERT and expand the list of known caspase motifs.
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, CB 7568, Chapel Hill, North Carolina 27514, United States.
authors.forename: Joana
authors.initials: J
authors.lastname: Soares
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Lowe
authors.forename: Michael B
authors.initials: MB
authors.lastname: Jarstfer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001224:Aspartic Acid / Q000235:genetics; D053178:Caspase 6 / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics; D053179:Caspase 7 / Q000737:chemistry* / Q000172:deficiency / Q000235:genetics; D020134:Catalytic Domain; D015536:Down-Regulation / Q000235:genetics; D018698:Glutamic Acid / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011817:Rabbits; D015398:Signal Transduction / Q000235:genetics; D013379:Substrate Specificity / Q000235:genetics; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000737:chemistry*
chemical_list: D001224:Aspartic Acid; D018698:Glutamic Acid; C509186:TERT protein, human; D019098:Telomerase; D053178:Caspase 6; D053179:Caspase 7