TERT suppresses apoptotis at a premitochondrial step by a mechanism requiring reverse transcriptase activity and 14-3-3 protein-binding ability.
The catalytic subunit of telomerase (TERT) is a reverse transcriptase (RT) that adds a six-base DNA repeat onto chromosome ends and prevents their shortening during successive cell divisions. Telomerase is associated with cell immortality and cancer, which may by related to the ability of TERT to prevent apoptosis by stabilizing telomeres. However, fundamental information concerning the antiapoptotic function of TERT is lacking, including whether RT activity and/or nuclear localization are required and where telomerase acts to suppress the cell death process. Here, we show that overexpression of wild-type human TERT in HeLa cells, and in a cells lacking TERT but containing the telomerase RNA template, increases their resistance to apoptosis induced by the DNA damaging agent etoposide or the bacterial alkaloid staurosporine. In contrast, TERT mutants with disruptions of either the RT domain or a 14-3-3 binding domain fail to protect cells against apoptosis, and overexpression of TERT in cells lacking the telomerase RNA template is also ineffective in preventing apoptosis. Additional findings show that TERT suppresses apoptosis at an early step before release of cytochrome c and apoptosis-inducing factor from mitochondria. We conclude that both RT activity and 14-3-3 protein binding ability are required for the antiapoptotic function of TERT in tumor cells and that TERT can suppress a nuclear signal(s) that is an essential component of apoptotic cascades triggered by diverse stimuli.
Zhang
Peisu
P
Laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, Maryland 21224, USA.
Chan
Sic L
SL
Fu
Weiming
W
Mendoza
Marty
M
Mattson
Mark P
MP
D048948:14-3-3 Proteins; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D051033:Apoptosis Inducing Factor; D001665:Binding Sites / Q000235:genetics; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005420:Flavoproteins / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation; D011485:Protein Binding; D012194:RNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism*
D048948:14-3-3 Proteins; C494829:AIFM1 protein, human; D000972:Antineoplastic Agents, Phytogenic; D051033:Apoptosis Inducing Factor; D003574:Cytochrome c Group; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005420:Flavoproteins; D008565:Membrane Proteins; D005047:Etoposide; D014446:Tyrosine 3-Monooxygenase; D012194:RNA-Directed DNA Polymerase; C509186:TERT protein, human; D019098:Telomerase; D019311:Staurosporine