title: Catalytically active telomerase holoenzyme is assembled in the dense fibrillar component of the nucleolus during S phase.
abstract: The maintenance of human telomeres requires the ribonucleoprotein enzyme telomerase, which is composed of telomerase reverse transcriptase (TERT), telomerase RNA component, and several additional proteins for assembly and activity. Telomere elongation by telomerase in human cancer cells involves multiple steps including telomerase RNA biogenesis, holoenzyme assembly, intranuclear trafficking, and telomerase recruitment to telomeres. Although telomerase has been shown to accumulate in Cajal bodies for association with telomeric chromatin, it is unclear where and how the assembly and trafficking of catalytically active telomerase is regulated in the context of nuclear architecture. Here, we show that the catalytically active holoenzyme is initially assembled in the dense fibrillar component of the nucleolus during S phase. The telomerase RNP is retained in nucleoli through the interaction of hTERT with nucleolin, a major nucleolar phosphoprotein. Upon association with TCAB1 in S phase, the telomerase RNP is transported from nucleoli to Cajal bodies, suggesting that TCAB1 acts as an S-phase-specific holoenzyme component. Furthermore, depletion of TCAB1 caused an increase in the amount of telomerase RNP associated with nucleolin. These results suggest that the TCAB1-dependent trafficking of telomerase to Cajal bodies occurs in a step separate from the holoenzyme assembly in nucleoli. Thus, we propose that the dense fibrillar component is the provider of active telomerase RNP for supporting the continued proliferation of cancer and stem cells.
authors: Department of Integrated Omics for Biomedical Science, Graduate School of Yonsei University, 134 Shinchon-dong, Seoul, 120-749, Korea.
authors: Ji Hoon
authors: JH
authors: Lee
authors: Yang Sin
authors: YS
authors: Lee
authors: Sun Ah
authors: SA
authors: Jeong
authors: Prabhat
authors: P
authors: Khadka
authors: Jürgen
authors: J
authors: Roth
authors: In Kwon
authors: IK
authors: Chung
mesh_terms: D045744:Cell Line, Tumor; D002466:Cell Nucleolus / Q000201:enzymology*; D005434:Flow Cytometry; D020035:Holoenzymes / Q000378:metabolism; D006801:Humans; D016196:S Phase; D019098:Telomerase / Q000378:metabolism*
chemical_list: D020035:Holoenzymes; D019098:Telomerase