TY - JOUR
T1 - Impaired telomere integrity and rRNA biogenesis in PARN‐deficient patients and knock‐out models
AU - Benyelles, Maname
AU - Episkopou, Harikleia
AU - O'Donohue, Marie‐Françoise
AU - Kermasson, Laëtitia
AU - Frange, Pierre
AU - Poulain, Florian
AU - Belen, Fatma Burcu
AU - Polat, Meltem
AU - Bole‐Feysot, Christine
AU - Langa‐Vives, Francina
AU - Gleizes, Pierre‐Emmanuel
AU - Villartay, Jean‐Pierre
AU - Callebaut, Isabelle
AU - Decottignies, Anabelle
AU - Revy, Patrick
N1 - Funding Information:
We thank the patients and their families for their contribution. We thank Jerry W. Shay and Woodring E. Wright for the kind gift of the Muntjac cells. P.R. is grateful to Prof. Alain Fischer for discussions, advice, and support. We acknowledge the excellent technical assistance of Alicia Fernandez for generating B-LCL (CRB, Imagine Institute, Paris, France) and Nikenza Viceconte for the hTR FISH. This work has been supported by institutional grants from INSERM, Ligue Nationale contre le Cancer (Equipe Labellisée La Ligue), Institut National du Cancer INCa, GIS-Institut des maladies rares, and FNRS (Fonds National de la Recherche Scientifique, Belgium). P.E.G. and M.F.O. are supported by Agence Nationale de la Recherche (ANR 2015 AAP générique CE12-0001-DBA Multigenes), and the EuroDBA project is funded by the ERA-NET program E-RAR3 (ANR-15-RAR3-0007-04). P.R. and M.F.O. are scientists from Centre National de la Recherche Scientifique (CNRS). H.E. and F.P. were supported by grants from the Télévie/FNRS and FRIA/FNRS. A.D. is a scientist from the FNRS.
Funding Information:
We thank the patients and their families for their contribution. We thank Jerry W. Shay and Woodring E. Wright for the kind gift of the Muntjac cells. P.R. is grateful to Prof. Alain Fischer for discussions, advice, and support. We acknowledge the excellent technical assistance of Alicia Fernandez for generating B-LCL (CRB, Imagine Institute, Paris, France) and Nikenza Viceconte for the hTR FISH. This work has been supported by institutional grants from INSERM, Ligue Nationale contre le Cancer (Equipe Labellisée La Ligue), Insti-tut National du Cancer INCa, GIS-Institut des maladies rares, and FNRS (Fonds National de la Recherche Scientifique, Belgium). P.E.G. and M.F.O. are supported by Agence Nationale de la Recherche (ANR 2015 AAP générique CE12-0001-DBA Multigenes), and the EuroDBA project is funded by the ERA-NET program E-RAR3 (ANR-15-RAR3-0007-04). P.R. and M.F.O. are scientists from Centre National de la Recherche Scientifique (CNRS). H.E. and F.P. were supported by grants from the Télévie/FNRS and FRIA/FNRS. A.D. is a scientist from the FNRS.
Publisher Copyright:
© 2019 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2019/7
Y1 - 2019/7
N2 - 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.
AB - 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.
KW - Høyeraal–Hreidarsson syndrome
KW - PARN
KW - p53
KW - rRNA
KW - shelterin
UR - http://www.scopus.com/inward/record.url?scp=85067393765&partnerID=8YFLogxK
U2 - 10.15252/emmm.201810201
DO - 10.15252/emmm.201810201
M3 - Article
SN - 1757-4676
VL - 11
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 7
M1 - e10201
ER -