Blood advances, volume 4, issue 12, pages 2717-2722
Chemical inhibition of PAPD5/7 rescues telomerase function and hematopoiesis in dyskeratosis congenita.
Shukla Siddharth
1, 2
,
Jeong Ho-Chang
3
,
Sturgeon Christopher M
3, 4
,
PARKER ROY T
1, 2
,
Batista Luis Francisco Zirnberger
3, 4
1
Department of Biochemistry, University of Colorado Boulder, Boulder, CO;
|
2
Howard Hughes Medical Institute, Chevy Chase, MD; and
|
3
Department of Medicine and
4
Center of Regenerative Medicine, Washington University in St. Louis, St. Louis, MO
Publication type: Journal Article
Publication date: 2020-06-19
PubMed ID:
32559291
Hematology
Abstract
Dyskeratosis congenita (DC) is a pediatric bone marrow failure syndrome caused by germline mutations in telomere biology genes. Mutations in DKC1 (the most commonly mutated gene in DC), the 3′ region of TERC, and poly(A)-specific ribonuclease (PARN) cause reduced levels of the telomerase RNA component (TERC) by reducing its stability and accelerating TERC degradation. We have previously shown that depleting wild-type DKC1 levels by RNA interference or expression of the disease-associated A353V mutation in the DKC1 gene leads to decay of TERC, modulated by 3′-end oligoadenylation by noncanonical poly(A) polymerase 5 (PAPD5) followed by 3′ to 5′ degradation by EXOSC10. Furthermore, the constitutive genetic silencing of PAPD5 is sufficient to rescue TERC levels, restore telomerase function, and elongate telomeres in DKC1_A353V mutant human embryonic stem cells (hESCs). Here, we tested a novel PAPD5/7 inhibitor (RG7834), which was originally discovered in screens against hepatitis B viral loads in hepatic cells. We found that treatment with RG7834 rescues TERC levels, restores correct telomerase localization in DKC1 and PARN-depleted cells, and is sufficient to elongate telomeres in DKC1_A353V hESCs. Finally, treatment with RG7834 significantly improved definitive hematopoietic potential from DKC1_A353V hESCs, indicating that the chemical inhibition of PAPD5 is a potential therapy for patients with DC and reduced TERC levels.
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- We do not take into account publications that without a DOI.
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- Statistics recalculated weekly.
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Shukla S. et al. Chemical inhibition of PAPD5/7 rescues telomerase function and hematopoiesis in dyskeratosis congenita. // Blood advances. 2020. Vol. 4. No. 12. pp. 2717-2722.
GOST all authors (up to 50)
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Shukla S., Jeong H., Sturgeon C. M., PARKER R. T., Batista L. F. Z. Chemical inhibition of PAPD5/7 rescues telomerase function and hematopoiesis in dyskeratosis congenita. // Blood advances. 2020. Vol. 4. No. 12. pp. 2717-2722.
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TY - JOUR
DO - 10.1182/bloodadvances.2020001848
UR - https://doi.org/10.1182%2Fbloodadvances.2020001848
TI - Chemical inhibition of PAPD5/7 rescues telomerase function and hematopoiesis in dyskeratosis congenita.
T2 - Blood advances
AU - Shukla, Siddharth
AU - Jeong, Ho-Chang
AU - Sturgeon, Christopher M
AU - PARKER, ROY T
AU - Batista, Luis Francisco Zirnberger
PY - 2020
DA - 2020/06/19 00:00:00
PB - American Society of Hematology
SP - 2717-2722
IS - 12
VL - 4
PMID - 32559291
SN - 2473-9537
ER -
Cite this
BibTex
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@article{2020_Shukla,
author = {Siddharth Shukla and Ho-Chang Jeong and Christopher M Sturgeon and ROY T PARKER and Luis Francisco Zirnberger Batista},
title = {Chemical inhibition of PAPD5/7 rescues telomerase function and hematopoiesis in dyskeratosis congenita.},
journal = {Blood advances},
year = {2020},
volume = {4},
publisher = {American Society of Hematology},
month = {jun},
url = {https://doi.org/10.1182%2Fbloodadvances.2020001848},
number = {12},
pages = {2717--2722},
doi = {10.1182/bloodadvances.2020001848}
}
Cite this
MLA
Copy
Shukla, Siddharth, et al. “Chemical inhibition of PAPD5/7 rescues telomerase function and hematopoiesis in dyskeratosis congenita..” Blood advances, vol. 4, no. 12, Jun. 2020, pp. 2717-2722. https://doi.org/10.1182%2Fbloodadvances.2020001848.