An Enhanced H/ACA RNP Assembly Mechanism for Human Telomerase RNA
Open accessAbstract
The integral telomerase RNA subunit templates the synthesis of telomeric repeats. The biological accumulation of human telomerase RNA (hTR) requires hTR H/ACA domain assembly with the same proteins that assemble on other human H/ACA RNAs. Despite this shared RNP composition, hTR accumulation is particularly sensitized to disruption by disease-linked H/ACA protein variants. We show that contrary to expectation, hTR-specific sequence requirements for biological accumulation do not act at an hTR-specific step of H/ACA RNP biogenesis; instead, they enhance hTR binding to the shared, chaperone-bound scaffold of H/ACA core proteins that mediates initial RNP assembly. We recapitulate physiological H/ACA RNP assembly with a preassembled NAF1/dyskerin/NOP10/NHP2 scaffold purified from cell extract and demonstrate that distributed sequence features of the hTR 3' hairpin synergize to improve scaffold binding. Our findings reveal that the hTR H/ACA domain is distinguished from other human H/ACA RNAs not by a distinct set of RNA-protein interactions but by an increased efficiency of RNP assembly. Our findings suggest a unifying mechanism for human telomerase deficiencies associated with H/ACA protein variants.
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Five of the seven identified LTL-associated loci contain genes (TERC, TERT, NAF1, OBFC1, RTEL1) known to be involved in telomere biology.
“Five of the loci contain genes (TERC, TERT, NAF1, OBFC1, RTEL1) that are known to be involved in telomere biology.”
From Identification of seven loci affecting mean telomere length and their association with disease (2013) · cites this paper as [20]
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References 49 · Cited by 76
- Authors
- Egan, E. D., & Collins, K.
- Affiliations
- University of California, Berkeley (US)
- Corresponding author
- Collins, Kathleen
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2012-07-01
- Volume
- 32
- Issue
- 13
- Pages
- 2428-2439
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC3434483
- OpenAlex
- W2153002514
- Cited by
- 76
- References
- 49
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 3 · 2023: 2 · 2022: 6 · 2021: 8 · 2020: 7 · 2019: 3 · 2018: 7 · 2017: 7 · 2016: 4 · 2015: 10 · 2014: 6 · 2013: 3 · 2012: 3
- FWCI
- 4.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular and Cellular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (HL079585)
- National Heart, Lung, and Blood Institute (HL079585, R01HL079585, R56HL079585)
- National Institute of General Medical Sciences (R01GM054198)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Keywords
- hTR, NAF1, dyskerin, NOP10, NHP2, RNA-protein interactions, telomerase deficiency
- MeSH terms
- Base Sequence, HeLa Cells, Humans, Models, Molecular, Nuclear Proteins, Nucleic Acid Conformation, Ribonucleoproteins, RNA, RNA Polymerase II, RNA Polymerase III, Ribonucleoproteins, Small Nuclear, Cell Cycle Proteins, Telomerase, Ribonucleoproteins, Small Nucleolar, Macromolecular Substances, Protein Interaction Domains and Motifs, Protein Multimerization, HEK293 Cells
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