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Posttranscriptional modulation of TERC by PAPD5 inhibition rescues hematopoietic development in dyskeratosis congenita
- Publication Year :
- 2019
- Publisher :
- American Society of Hematology, 2019.
-
Abstract
- Reduced levels of TERC, 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 PAPD5, or the exosome RNA degradation complex, partially restores TERC levels in immortalized DKC1 mutant cells, but it remains unknown if modulation of posttranscriptional processing of TERC 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 EXOSC3 or PAPD5 levels in DKC1 mutant hESCs led to functional improvements in TERC levels and telomerase activity, with concomitant telomere elongation and reduced levels of DNA damage signaling. Interestingly, the silencing of PAPD5, but not EXOSC3, significantly restored definitive hematopoietic potential in DKC1 mutant cells. Mechanistically, we show that PAPD5 inhibition is sustained in differentiated CD34+ cells, with a concomitant increase in mature, functional, forms of TERC, indicating that regulation of PAPD5 is a potential strategy to reverse hematologic dysfunction in DC patients.
- Subjects :
- 0301 basic medicine
Telomerase
Hematopoiesis and Stem Cells
Immunology
CD34
Cell Cycle Proteins
Biology
medicine.disease_cause
Biochemistry
Dyskerin
Dyskeratosis Congenita
03 medical and health sciences
Telomerase RNA component
0302 clinical medicine
medicine
Gene silencing
Humans
RNA Processing, Post-Transcriptional
Embryonic Stem Cells
Mutation
Exosome Multienzyme Ribonuclease Complex
Nuclear Proteins
RNA-Binding Proteins
RNA Nucleotidyltransferases
Cell Biology
Hematology
Telomere
medicine.disease
Cell biology
Hematopoiesis
030104 developmental biology
030220 oncology & carcinogenesis
RNA
Dyskeratosis congenita
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....cc8601db4e21e086e9a2e1b16bfac888