Contributors: Genome dynamics in the immune system (Equipe Inserm U1163); Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163); Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité); Université Catholique de Louvain = Catholic University of Louvain (UCL); Laboratoire de biologie moléculaire eucaryote (LBME); Université Toulouse III - Paul Sabatier (UT3); Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre de Biologie Intégrative (CBI); Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS); Hôpital Necker - Enfants Malades AP-HP; Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP); Infection à VIH, réservoirs, diversité génétique et résistance aux antirétroviraux (ARV) (EA 7327); Université Paris Descartes - Paris 5 (UPD5); Başkent University Hospital Adana, Turkey; Pamukkale University; Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité); Centre d'Ingénierie génétique murine - Mouse Genetics Engineering Center (CIGM); Institut Pasteur Paris (IP); Institut de minéralogie, de physique des matériaux et de cosmochimie (IMPMC); Muséum national d'Histoire naturelle (MNHN)-Institut de recherche pour le développement IRD : UR206-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS); 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.; ANR-15-CE12-0001,DBA-MULTIGENES,DBA-MULTIGENES: identification et caractérisation de gènes candidats pour la découverte de nouveaux mécanismes physiopathologiques à l'origine de l'anémie de Blackfan-Diamond.(2015); ANR-15-RAR3-0007,EuroDBA,The European Diamond-Blackfan Anemia Consortium(2015)
نبذة مختصرة : International audience ; 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.
Processing Request
No Comments.