Posttranscriptional modulation of TERC by PAPD5 inhibition rescues hematopoietic development in dyskeratosis congenita.

Reduced levels of , the telomerase RNA component, cause dyskeratosis congenita (DC) in patients harboring mutations in TERC, PARN, NOP10, NHP2, NAF1, or DKC1. Inhibition of the noncanonical poly(A) polymerase , or the exosome RNA degradation complex, partially restores levels in immortalized DKC1 mutant cells, but it remains unknown if modulation of posttranscriptional processing of could improve hematopoietic output in DC. We used human embryonic stem cells (hESCs) with a common dyskerin mutation (DKC1_A353V), which have defective telomere maintenance and reduced definitive hematopoietic potential, to understand the effects of reducing EXOSC3 activity, or silencing PAPD5-mediated oligoadenylation, on hematopoietic progenitor specification and function in DC. Reduction of or levels in DKC1 mutant hESCs led to functional improvements in levels and telomerase activity, with concomitant telomere elongation and reduced levels of DNA damage signaling. Interestingly, the silencing of , but not , significantly restored definitive hematopoietic potential in DKC1 mutant cells. Mechanistically, we show that inhibition is sustained in differentiated CD34 cells, with a concomitant increase in mature, functional, forms of , indicating that regulation of is a potential strategy to reverse hematologic dysfunction in DC patients.