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

Area of Science:

• Molecular Biology
• Genetics
• Cell Biology

Background:

• Poly(A)-specific ribonuclease (PARN) is crucial for mRNA turnover and telomerase RNA (hTR) maturation.
• Mutations in PARN are linked to Høyeraal-Hreidarsson (HH) syndrome, a severe telomere biology disorder.
• The full impact of PARN deficiency on telomere-related gene expression was not well understood.

Purpose of the Study:

• To investigate the effects of PARN deficiency on telomere length, stability, and the expression of telomere-related genes.
• To explore the consequences of PARN deficiency on ribosomal RNA biogenesis and DKC1 mRNA expression.
• To elucidate the role of p53 activation in PARN-deficient cells.

Main Methods:

• Analysis of cells from HH individuals with novel PARN mutations.
• Utilizing a human PARN knock-out (KO) cell line with inducible PARN complementation.
• Assessing telomere length and stability, gene expression (shelterin, DKC1), and ribosomal RNA biogenesis in patient and KO cells, including heterozygous Parn KO mice.

Main Results:

• PARN deficiency was found to impair telomere length and stability.
• Expression of shelterin component transcripts (TRF1, TRF2, TPP1, RAP1, POT1) was down-regulated in PARN-deficient cells.
• PARN deficiency led to decreased ribosomal RNA biogenesis and DKC1 mRNA down-regulation, mediated by p53 activation. Homozygous Parn KO resulted in embryonic lethality.

Conclusions:

• PARN deficiency has pleiotropic cellular effects beyond hTR regulation, impacting telomere maintenance and gene expression.
• The study refines understanding of the molecular mechanisms underlying HH syndrome and telomere biology disorders.
• PARN plays a critical role in maintaining genomic stability and cellular homeostasis, with its deficiency leading to severe developmental consequences.