Apr 22, 2015

Poly(A)-specific ribonuclease deficiency impacts telomere biology and causes dyskeratosis congenita

The Journal of Clinical Investigation
Hemanth TummalaInderjeet Dokal


Dyskeratosis congenita (DC) and related syndromes are inherited, life-threatening bone marrow (BM) failure disorders, and approximately 40% of cases are currently uncharacterized at the genetic level. Here, using whole exome sequencing (WES), we have identified biallelic mutations in the gene encoding poly(A)-specific ribonuclease (PARN) in 3 families with individuals exhibiting severe DC. PARN is an extensively characterized exonuclease with deadenylation activity that controls mRNA stability in part and therefore regulates expression of a large number of genes. The DC-associated mutations identified affect key domains within the protein, and evaluation of patient cells revealed reduced deadenylation activity. This deadenylation deficiency caused an early DNA damage response in terms of nuclear p53 regulation, cell-cycle arrest, and reduced cell viability upon UV treatment. Individuals with biallelic PARN mutations and PARN-depleted cells exhibited reduced RNA levels for several key genes that are associated with telomere biology, specifically TERC, DKC1, RTEL1, and TERF1. Moreover, PARN-deficient cells also possessed critically short telomeres. Collectively, these results identify a role for PARN in telomere maintenance and d...Continue Reading

Mentioned in this Paper

TP53 gene
Telomere Lengthening
Telomerase RNA Component
Regulation of Biological Process
PARN protein, human
Bone Marrow
Tertiary Protein Structure
Response to DNA Damage Stimulus
TERF1 wt Allele

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