title: Telomerase recruitment requires both TCAB1 and Cajal bodies independently.
abstract: The ability of most cancer cells to grow indefinitely relies on the enzyme telomerase and its recruitment to telomeres. In human cells, recruitment depends on the Cajal body RNA chaperone TCAB1 binding to the RNA subunit of telomerase (hTR) and is also thought to rely on an N-terminal domain of the catalytic subunit, hTERT. We demonstrate that coilin, an essential structural component of Cajal bodies, is required for endogenous telomerase recruitment to telomeres but that overexpression of telomerase can compensate for Cajal body absence. In contrast, recruitment of telomerase was sensitive to levels of TCAB1, and this was not rescued by overexpression of telomerase. Thus, although Cajal bodies are important for recruitment, TCAB1 has an additional role in this process that is independent of these structures. TCAB1 itself localizes to telomeres in a telomerase-dependent but Cajal body-independent manner. We identify a point mutation in hTERT that largely abolishes recruitment yet does not affect association of telomerase with TCAB1, suggesting that this region mediates recruitment by an independent mechanism. Our results demonstrate that telomerase has multiple independent requirements for recruitment to telomeres and that the function of TCAB1 is to directly transport telomerase to telomeres.
authors.affiliation: Children's Medical Research Institute and Faculty of Medicine, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: J Lewis
authors.initials: JL
authors.lastname: Stern
authors.forename: Katherine G
authors.initials: KG
authors.lastname: Zyner
authors.forename: Hilda A
authors.initials: HA
authors.lastname: Pickett
authors.forename: Scott B
authors.initials: SB
authors.lastname: Cohen
authors.forename: Tracy M
authors.initials: TM
authors.lastname: Bryan
mesh_terms: D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020541:Coiled Bodies / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008954:Models, Biological; D018832:Molecular Chaperones; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D054730:Protein Interaction Domains and Motifs; D034741:RNA, Small Interfering / Q000235:genetics; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016615:Telomere / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; D018832:Molecular Chaperones; D050505:Mutant Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C068921:p80-coilin; D019098:Telomerase; C535133:WRAP53 protein, human