Abstract
PARN loss-of-function mutations cause a severe form of the hereditary disease dyskeratosis congenita (DC). PARN deficiency affects the stability of non-coding RNAs such as human telomerase RNA (hTR), but these effects do not explain the severe disease in patients. We demonstrate that PARN deficiency affects the levels of numerous miRNAs in human cells. PARN regulates miRNA levels by stabilizing either mature or precursor miRNAs by removing oligo(A) tails added by the poly(A) polymerase PAPD5, which if remaining recruit the exonuclease DIS3L or DIS3L2 to degrade the miRNA. PARN knockdown destabilizes multiple miRNAs that repress p53 translation, which leads to an increase in p53 accumulation in a Dicer-dependent manner, thus explaining why PARN-defective patients show p53 accumulation. This work also reveals that DIS3L and DIS3L2 are critical 3' to 5' exonucleases that regulate miRNA stability, with the addition and removal of 3' end extensions controlling miRNA levels in the cell.
Keywords:
3′ end modification; DIS3L; DIS3L2; PAPD5; PARN; cancer; dyskeratosis congenita; miRNA; non-coding RNA degradation; p53.
Copyright © 2019 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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3' Untranslated Regions
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Antineoplastic Agents / pharmacology
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Cell Survival
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DEAD-box RNA Helicases / genetics
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DEAD-box RNA Helicases / metabolism
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Doxorubicin / pharmacology
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Etoposide / pharmacology
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Exoribonucleases / genetics
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Exoribonucleases / metabolism*
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Female
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Gene Expression Regulation, Neoplastic
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HCT116 Cells
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HeLa Cells
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Humans
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MicroRNAs / genetics
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MicroRNAs / metabolism*
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Polyadenylation
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RNA Nucleotidyltransferases / genetics
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RNA Nucleotidyltransferases / metabolism
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RNA Stability*
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Ribonuclease III / genetics
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Ribonuclease III / metabolism
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Ribonucleases / genetics
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Ribonucleases / metabolism
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Signal Transduction
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
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Uterine Cervical Neoplasms / drug therapy
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Uterine Cervical Neoplasms / enzymology*
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Uterine Cervical Neoplasms / genetics
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Uterine Cervical Neoplasms / pathology
Substances
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3' Untranslated Regions
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Antineoplastic Agents
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MicroRNAs
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TP53 protein, human
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Tumor Suppressor Protein p53
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Etoposide
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Doxorubicin
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RNA Nucleotidyltransferases
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TENT4B protein, human
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DIS3L protein, human
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DIS3L2 protein, human
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Exoribonucleases
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Ribonucleases
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poly(A)-specific ribonuclease
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DICER1 protein, human
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Ribonuclease III
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DEAD-box RNA Helicases