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EMBO Mol Med. 2019 Jul;11(7):e10201. doi: 10.15252/emmm.201810201. Epub 2019 Jun 6.

Impaired telomere integrity and rRNA biogenesis in PARN-deficient patients and knock-out models.

Author information

1
Laboratory of Genome Dynamics in the Immune System, INSERM, UMR 1163, Paris, France.
2
Laboratoire labellisé Ligue, Imagine Institute, Paris Descartes-Sorbonne Paris Cite University, Paris, France.
3
de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
4
Laboratoire de Biologie Moléculaire Eucaryote, Centre de Biologie Intégrative (CBI), CNRS, UPS, Université de Toulouse, Toulouse, France.
5
EA 7327, Université Paris Descartes, Sorbonne Paris-Cité, Paris, France.
6
Laboratoire de Microbiologie clinique & Unité d'Immunologie, Hématologie et Rhumatologie Pédiatriques, AP-HP, Hôpital Necker, Enfants Malades, Paris, France.
7
Pediatric Hematology, Faculty of Medicine, Baskent University, Ankara, Turkey.
8
Pediatric Infectious Diseases, Department of Pediatric Infectious Diseases, Pamukkale University Medical Faculty, Denizli, Turkey.
9
INSERM, UMR 1163, Genomics platform, Imagine Institute, Paris Descartes-Sorbonne Paris Cité University, Paris, France.
10
Genomic Core Facility, Imagine Institute-Structure Fédérative de Recherche Necker, INSERM U1163, Paris, France.
11
Centre d'Ingénierie Génétique Murine, Institut Pasteur, Paris, France.
12
Muséum National d'Histoire Naturelle, UMR CNRS 7590, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, IMPMC, Sorbonne Université, Paris, France.

Abstract

PARN, poly(A)-specific ribonuclease, regulates the turnover of mRNAs and the maturation and stabilization of the hTR RNA component of telomerase. Biallelic PARN mutations were associated with Høyeraal-Hreidarsson (HH) syndrome, a rare telomere biology disorder that, because of its severity, is likely not exclusively due to hTR down-regulation. Whether PARN deficiency was affecting the expression of telomere-related genes was still unclear. Using cells from two unrelated HH individuals carrying novel PARN mutations and a human PARN knock-out (KO) cell line with inducible PARN complementation, we found that PARN deficiency affects both telomere length and stability and down-regulates the expression of TRF1, TRF2, TPP1, RAP1, and POT1 shelterin transcripts. Down-regulation of dyskerin-encoding DKC1 mRNA was also observed and found to result from p53 activation in PARN-deficient cells. We further showed that PARN deficiency compromises ribosomal RNA biogenesis in patients' fibroblasts and cells from heterozygous Parn KO mice. Homozygous Parn KO however resulted in early embryonic lethality that was not overcome by p53 KO. Our results refine our knowledge on the pleiotropic cellular consequences of PARN deficiency.

KEYWORDS:

PARN ; rRNA ; Høyeraal-Hreidarsson syndrome; p53; shelterin

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