title: Telomerase reverse transcriptase promotes cancer cell proliferation by augmenting tRNA expression.
abstract: Transcriptional reactivation of telomerase reverse transcriptase (TERT) reconstitutes telomerase activity in the majority of human cancers. Here, we found that ectopic TERT expression increases cell proliferation, while acute reductions in TERT levels lead to a dramatic loss of proliferation without any change in telomere length, suggesting that the effects of TERT could be telomere independent. We observed that TERT determines the growth rate of cancer cells by directly regulating global protein synthesis independently of its catalytic activity. Genome-wide TERT binding across 5 cancer cell lines and 2 embryonic stem cell lines revealed that endogenous TERT, driven by mutant promoters or oncogenes, directly associates with the RNA polymerase III (pol III) subunit RPC32 and enhances its recruitment to chromatin, resulting in increased RNA pol III occupancy and tRNA expression in cancers. TERT-deficient mice displayed marked delays in polyomavirus middle T oncogene-induced (PyMT-induced) mammary tumorigenesis, increased survival, and reductions in tRNA levels. Ectopic expression of either RPC32 or TERT restored tRNA levels and proliferation defects in TERT-depleted cells. Finally, we determined that levels of TERT and tRNA correlated in breast and liver cancer samples. Together, these data suggest the existence of a unifying mechanism by which TERT enhances translation in cells to regulate cancer cell proliferation.
authors.forename: Ekta
authors.initials: E
authors.lastname: Khattar
authors.forename: Pavanish
authors.initials: P
authors.lastname: Kumar
authors.forename: Chia Yi
authors.initials: CY
authors.lastname: Liu
authors.forename: Semih Can
authors.initials: SC
authors.lastname: Akıncılar
authors.forename: Anandhkumar
authors.initials: A
authors.lastname: Raju
authors.forename: Manikandan
authors.initials: M
authors.lastname: Lakshmanan
authors.forename: Julien Jean Pierre
authors.initials: JJ
authors.lastname: Maury
authors.forename: Yu
authors.initials: Y
authors.lastname: Qiang
authors.forename: Shang
authors.initials: S
authors.lastname: Li
authors.forename: Ern Yu
authors.initials: EY
authors.lastname: Tan
authors.forename: Kam M
authors.initials: KM
authors.lastname: Hui
authors.forename: Ming
authors.initials: M
authors.lastname: Shi
authors.forename: Yuin Han
authors.initials: YH
authors.lastname: Loh
authors.forename: Vinay
authors.initials: V
authors.lastname: Tergaonkar
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D014176:Protein Biosynthesis; D054730:Protein Interaction Domains and Motifs; D012320:RNA Polymerase III / Q000378:metabolism; D012343:RNA, Transfer / Q000235:genetics* / Q000378:metabolism; D019098:Telomerase / Q000502:physiology*
chemical_list: D012343:RNA, Transfer; C569418:POLR3G protein, human; C509186:TERT protein, human; D019098:Telomerase; D012320:RNA Polymerase III