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Disruption of Telomerase RNA Maturation Kinetics Precipitates Disease
Roake, Caitlin M. Chakravarthy, Ananya L. Ferrell, James E. Raffa, Grazia D. Artandi, Steven E.
Roake, Caitlin M.
Chakravarthy, Ananya L.
Ferrell, James E.
Raffa, Grazia D.
Artandi, Steven E.
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Post-print
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2019-05-16
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Cancer and Cellular Biology
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https://doi.org/10.1016/j.molcel.2019.02.033
Abstract
Mutations in RNA-processing enzymes are increasingly linked to human disease. Telomerase RNA and related noncoding RNAs require 3′ end-processing steps, including oligoadenylation. Germline mutations in poly(A)ribonuclease (PARN) cause accumulation of extended human telomerase RNA (hTR) species and precipitate dyskeratosis congenita and pulmonary fibrosis. Here, we develop nascent RNAend-seq to measure processing rates of RNA precursors. We find that mature hTR derives from extended precursors but that in PARN-mutant cells hTR maturation kinetically stalls and unprocessed precursors are degraded. Loss of poly(A)polymerase PAPD5 in PARN-mutant cells accelerates hTR maturation and restores hTR processing, indicating that oligoadenylation and deadenylation set rates of hTR maturation. The H/ACA domain mediates hTR maturation by precisely defining the 3′ end, recruiting poly(A)polymerase activity, and conferring sensitivity to PARN regulation. These data reveal a feedforward circuit in which post-transcriptional oligoadenylation controls RNA maturation kinetics. Similar alterations in RNA processing rates may contribute to mechanisms of RNA-based human disease.
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Roake CM, Chen L, Chakravarthy AL, Ferrell JE, Raffa GD, Artandi SE. Disruption of Telomerase RNA Maturation Kinetics Precipitates Disease. Mol. Cell. 2019 May 16;74(4):688-700.e3. doi:10.1016/j.molcel.2019.02.033.
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Cell Press
© This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/
© This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/
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Molecular Cell, Vol. 74, Iss. 4
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