Blood, volume 133, issue 12, pages 1308-1312
Posttranscriptional modulation of TERC by PAPD5 inhibition rescues hematopoietic development in dyskeratosis congenita.
Fok Wilson Chun
1
,
Shukla Siddharth
2
,
Vessoni Alexandre Teixeira
1
,
Brenner Kirsten Ann
1
,
Parker Roy
2, 3
,
Sturgeon Christopher M
1, 4, 5
,
Batista Luis Francisco Zirnberger
1, 4, 5
1
Division of Hematology, Department of Medicine, and
2
Department of Biochemistry, University of Colorado Boulder, Boulder, CO;
|
3
Howard Hughes Medical Institute, Chevy Chase, MD; and
|
4
Department of Developmental Biology and
5
Center of Regenerative Medicine, Washington University in St. Louis, St. Louis, MO
Publication type: Journal Article
Publication date: 2019-03-21
PubMed ID:
30728146
Biochemistry
Cell Biology
Immunology
Hematology
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.
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- We do not take into account publications that without a DOI.
- Statistics recalculated only for publications connected to researchers, organizations and labs registered on the platform.
- Statistics recalculated weekly.
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Fok W. C. et al. Posttranscriptional modulation of TERC by PAPD5 inhibition rescues hematopoietic development in dyskeratosis congenita. // Blood. 2019. Vol. 133. No. 12. pp. 1308-1312.
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Fok W. C., Shukla S., Vessoni A. T., Brenner K. A., Parker R., Sturgeon C. M., Batista L. F. Z. Posttranscriptional modulation of TERC by PAPD5 inhibition rescues hematopoietic development in dyskeratosis congenita. // Blood. 2019. Vol. 133. No. 12. pp. 1308-1312.
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TY - JOUR
DO - 10.1182/blood-2018-11-885368
UR - https://doi.org/10.1182%2Fblood-2018-11-885368
TI - Posttranscriptional modulation of TERC by PAPD5 inhibition rescues hematopoietic development in dyskeratosis congenita.
T2 - Blood
AU - Fok, Wilson Chun
AU - Shukla, Siddharth
AU - Vessoni, Alexandre Teixeira
AU - Brenner, Kirsten Ann
AU - Parker, Roy
AU - Sturgeon, Christopher M
AU - Batista, Luis Francisco Zirnberger
PY - 2019
DA - 2019/03/21 00:00:00
PB - American Society of Hematology
SP - 1308-1312
IS - 12
VL - 133
PMID - 30728146
SN - 0006-4971
SN - 1528-0020
ER -
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@article{2019_Fok,
author = {Wilson Chun Fok and Siddharth Shukla and Alexandre Teixeira Vessoni and Kirsten Ann Brenner and Roy Parker and Christopher M Sturgeon and Luis Francisco Zirnberger Batista},
title = {Posttranscriptional modulation of TERC by PAPD5 inhibition rescues hematopoietic development in dyskeratosis congenita.},
journal = {Blood},
year = {2019},
volume = {133},
publisher = {American Society of Hematology},
month = {mar},
url = {https://doi.org/10.1182%2Fblood-2018-11-885368},
number = {12},
pages = {1308--1312},
doi = {10.1182/blood-2018-11-885368}
}
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MLA
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Fok, Wilson Chun, et al. “Posttranscriptional modulation of TERC by PAPD5 inhibition rescues hematopoietic development in dyskeratosis congenita..” Blood, vol. 133, no. 12, Mar. 2019, pp. 1308-1312. https://doi.org/10.1182%2Fblood-2018-11-885368.