mRNA deadenylation and telomere disease

Abstract

Dyskeratosis congenita (DC) is an inherited BM failure disorder that is associated with mutations in genes involved with telomere function and maintenance; however, the genetic cause of many instances of DC remains uncharacterized. In this issue of the JCI, Tummala and colleagues identify mutations in the gene encoding the poly(A)-specific ribonuclease (PARN) in individuals with a severe form of DC in three different families. PARN deficiency resulted in decreased expression of genes required for telomere maintenance and an aberrant DNA damage response, including increased levels of p53. Together, the results of this study support PARN as a DC-associated gene and suggest a potential link between p53 and telomere shortening.

Figure 1. Possible effects of PARN depletion on telomeres.

(A) DNA damage in replicating WT cells causes increased levels of the tumor suppressor p53, which in turn induces p21 and the DNA damage response. p53 also activates the PARN deadenylase, which destabilizes p53 mRNA, thereby reducing p53 levels (17). (B) In the absence of PARN, p53 levels can increase unchecked and lead to inhibition of telomere-related genes and short telomeres. Shortened telomeres exacerbate the DNA damage response, further increasing p53 levels, and thereby activating a cycle that leads to short telomeres and cell cycle arrest in rapidly replicating cells — a hallmark of DC pathobiology.