TY - JOUR
T1 - Posttranscriptional modulation of TERC by PAPD5 inhibition rescues hematopoietic development in dyskeratosis congenita
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
N1 - Funding Information:
This work was supported by a National Institutes of Health, National Heart, Lung, and Blood Institute T32 training grant in molecular hematology (HL007088 [W.C.F.]), the Philip Majerus Fellowship Fund (A.T.V.), the National Science Foundation (K.A.B.), Howard Hughes Medical Institute (R.P. and S.S.), National Institutes of Health, National Institute of General Medical Sciences grant R01GM45443 (R.P. and S.S.), an American Society of Hematology Scholar Award (C.M.S.), National Institutes of Health, National Heart, Lung, and Blood Institute grants 4R00HL114732 and 1R01HL137793 (L.F.Z.B.), and grants from the V Foundation for Cancer Research (L.F.Z.B.), the Edward Mallinckrodt Jr Foundation (L.F.Z.B.), the AA&MDS International Foundation (L.F.Z.B.), the CONCERN Foundation (L.F.Z.B.), the American Federation for Aging Research (L.F.Z.B.), the Longer Life Foundation (L.F.Z.B.), the Center for Regenerative Medicine at Washington University in St. Louis (L.F.Z.B.), and a grant from the Department of Defense Bone Marrow Failure Research Program (BM160054 [L.F.Z.B. and C.M.S.]).
Publisher Copyright:
© 2019 by The American Society of Hematology.
PY - 2019/3/21
Y1 - 2019/3/21
N2 - 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 CD341 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.
AB - 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 CD341 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.
UR - http://www.scopus.com/inward/record.url?scp=85063635602&partnerID=8YFLogxK
U2 - 10.1182/blood-2018-11-885368
DO - 10.1182/blood-2018-11-885368
M3 - Article
C2 - 30728146
AN - SCOPUS:85063635602
SN - 0006-4971
VL - 133
SP - 1308
EP - 1312
JO - Blood
JF - Blood
IS - 12
ER -