Telomerase RNA deficiency in peripheral blood mononuclear cells in X-linked dyskeratosis congenita

Wong, Judy M.Y.; Kyasa, Mouhammed J.; Hutchins, Laura; Collins, Kathleen

doi:10.1007/s00439-004-1178-7

Cited by 52 publications

(53 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Elucidation of the requirements for human telomerase RNP biogenesis will bring insights for disease therapy, because differences that distinguish hTR from H/ACA snoRNAs and scaRNAs must somehow give rise to the specificity of telomerase deficiency in patients with altered dyskerin (30,44). We first suspected that our original model for hTR 5Ј hairpin folding was incorrect, based on the potential for a more canonical 5Ј hairpin that satisfied the limited amount of structural data on hTR H/ACA motif folding in vivo (1,37).…”

Section: Discussionmentioning

confidence: 99%

Specificity and Stoichiometry of Subunit Interactions in the Human Telomerase Holoenzyme Assembled In Vivo

Egan

Collins

2010

Molecular and Cellular Biology

Self Cite

100

View full text Add to dashboard Cite

The H/ACA motif of human telomerase RNA (hTR) directs specific pathways of endogenous telomerase holoenzyme assembly, function, and regulation. Similarities between hTR and other H/ACA RNAs have been established, but differences have not been explored even though unique features of hTR H/ACA RNP assembly give rise to telomerase deficiency in human disease. Here, we define hTR H/ACA RNA and RNP architecture using RNA accumulation, RNP affinity purification, and primer extension activity assays. First, we evaluate alternative folding models for the hTR H/ACA motif 5 hairpin. Second, we demonstrate an unanticipated and surprisingly general asymmetry of 5 and 3 hairpin requirements for H/ACA RNA accumulation. Third, we establish that hTR assembles not one but two sets of all four of the H/ACA RNP core proteins, dyskerin, NOP10, NHP2, and GAR1. Fourth, we address a difference in predicted specificities of hTR association with the holoenzyme subunit WDR79/TCAB1. Together, these results complete the analysis of hTR elements required for active RNP biogenesis and define the interaction specificities and stoichiometries of all functionally essential human telomerase holoenzyme subunits. This study uncovers unexpected similarities but also differences between telomerase and other H/ACA RNPs that allow a unique specificity of telomerase biogenesis and regulation.

show abstract

Section: Discussionmentioning

confidence: 99%

Specificity and Stoichiometry of Subunit Interactions in the Human Telomerase Holoenzyme Assembled In Vivo

Egan

Collins

2010

Molecular and Cellular Biology

Self Cite

100

View full text Add to dashboard Cite

show abstract

“…Whole cell lysate from treated cells was electrophoresed on SDS-PAGE gel, transferred and subsequently blotted with antibodies against p53 (Cell Signaling) and β-actin (Sigma), as previously described (20). The membranes were immunoblotted with the appropriate horseradish peroxidase-conjugated secondary antibody, followed by ECL Plus (Amersham) for detection on Kodak X-ray films.…”

Section: Western Blot Assaysmentioning

confidence: 99%

Telomerase Inhibition Potentiates the Effects of Genotoxic Agents in Breast and Colorectal Cancer Cells in a Cell Cycle–Specific Manner

2010

View full text Add to dashboard Cite

Previous studies have shown that telomerase facilitates DNA-damage repair and cell survival following stress. It is not clear how telomerase promotes DNA repair, or whether short-term telomerase inhibition, combined with genotoxic stress, can be exploited for cancer therapy. Here, we show that transient inhibition of telomerase activity by the specific inhibitor, GRN163L, increases the cytotoxicity of some, but not all, DNA-damaging agents. Such synergistic inhibition of growth requires the use of DNA-damaging agents that are toxic in the S/G 2 phase of the cell cycle. Notably, inhibition of Ataxia Telangiectasia Mutated (ATM) kinase, together with telomerase inhibition, synergistically increases the cytotoxicity induced by the G 2 -specific topoisomerase II inhibitor etoposide. By varying the timing of telomerase inhibition, relative to the timing of DNA damage, it is apparent that the prosurvival functions of telomerase occur at early stages of DNA damage recognition and repair. Our results suggest that the protective role of telomerase in cell cycle-restricted DNA damage repair could be exploited for combined anticancer chemotherapy. Cancer Res; 70(21); 8684-94. ©2010 AACR.

show abstract

“…Numerous diseaselinked single amino acid changes in dyskerin have been reported, which cluster in regions of the protein separate from the surfaces crucial for H/ACA RNP subunit interactions or catalytic activity (Rashid et al, 2006). Primary cells from X-linked DC patients have about one-fifth of the wild-type level of hTR, but they show no obvious change in the accumulation levels of other H/ACA-motif RNAs or their processing targets (Mitchell et al, 1999b;Wong et al, 2004;Wong and Collins, 2006). X-linked DC patient cells that express hTERT fail to elongate telomeres, unlike family-matched control cells (Wong and Collins, 2006).…”

Section: Human Telomerase Deficiencymentioning

confidence: 99%

Physiological assembly and activity of human telomerase complexes

Collins

2008

Mechanisms of Ageing and Development

Self Cite

104

View full text Add to dashboard Cite

Telomerase is a specialized reverse transcriptase conserved throughout almost all eukaryotic life. It plays a fundamental role in genome maintenance, adding back the telomeric DNA repeats lost from chromosome ends due to incomplete replication or damage. The protein and RNA subunits of telomerase fold and function in a co-dependent manner to establish a high fidelity of telomeric repeat synthesis. Over the past two decades, studies of telomerase have uncovered previously unanticipated levels of complexity in its assembly, activity and regulation. This review describes the current understanding of telomerase in humans, with particular focus on telomerase biogenesis and regulation in its cellular context.

show abstract

Telomerase RNA deficiency in peripheral blood mononuclear cells in X-linked dyskeratosis congenita

Cited by 52 publications

References 31 publications

Specificity and Stoichiometry of Subunit Interactions in the Human Telomerase Holoenzyme Assembled In Vivo

Specificity and Stoichiometry of Subunit Interactions in the Human Telomerase Holoenzyme Assembled In Vivo

Telomerase Inhibition Potentiates the Effects of Genotoxic Agents in Breast and Colorectal Cancer Cells in a Cell Cycle–Specific Manner

Physiological assembly and activity of human telomerase complexes

Contact Info

Product

Resources

About