PARN - A Tale of A de-Tailor : Functional importance of poly(A) degradation in developmental and telomere biology disorders

Sammanfattning: Poly(A)-specific ribonuclease (PARN) is a eukaryotic 3’-5’exoribonuclease that removes poly(A) tails of many coding and non-coding RNAs. In this thesis, we have studied the physiological role of PARN. We have found that genetic lesions in the human PARN gene are associated with a spectrum of human developmental disorders, including telomere biology disorders (TBDs). TBDs encompass a spectrum of developmental disorders associated with telomere dysfunction and include idiopathic pulmonary fibrosis (IPF), aplastic anaemic (AA), dyskeratosis congenita (DC) and Hoyeraal-Hreidarsson syndrome (HHS). Patients with mono-allelic mutations in PARN suffer from developmental and neurological disorders, whereas bi-allelic mutations are associated with severe disorders, e.g., DC or HHS.Transcriptome analysis revealed that PARN deficient patients were affected in a number of cellular pathways. The most affected were the ribosome/translation, cell-cell adhesion, cell cycle and cell signaling pathways. We also found that PARN deficient patients were defective in the biogenesis of a large number of non-coding RNAs (ncRNAs), including snoRNAs, scaRNAs, miRNAs and rRNAs. Deficiency in snoRNA and rRNA biogenesis correlated with blood disorders and/or bone marrow failure. PARN deficient patients also displayed defects in the maturation of the telomerase RNA component that correlated with telomere shortening.To further understand the physiological role of PARN in TBDs over generations and throughout the life span of an organism, we have established a parn loss-of-function zebrafish model, which recapitulates TBD phenotypes in human patients. In keeping with the human patients, homozygous parn deficient fish exhibited aberrant snoRNA profile, perturbed telomerase RNA maturation and short telomeres. In addition, we found that the zygotic parn mutant fish exhibited a spectrum of developmental defects from early embryogenesis to adult stage. The whole array of disease phenotypes observed in PARN deficient human patients and the parn loss-of-function zebrafish model indicate that PARN has essential roles in regulating growth and development throughout the life of an organism.