TY - JOUR
T1 - Chemical inhibition of PAPD5/7 rescues telomerase function and hematopoiesis in dyskeratosis congenita
AU - Shukla, Siddharth
AU - Jeong, Ho Chang
AU - Sturgeon, Christopher M.
AU - Parker, Roy
AU - Batista, Luis Francisco Zirnberger
N1 - Funding Information:
R.P. and S.S. are supported by the Howard Hughes Medical Institute. H.-C.J. and L.F.Z.B. are supported by the National Heart, Lung, and Blood Institute, National Institutes of Health (1R01HL137793), and grants from the Center for Regenerative Medicine at Washington University in St. Louis, the Siteman Cancer Center, and the American Cancer Society.
Publisher Copyright:
© 2020 by The American Society of Hematology.
PY - 2020/6/23
Y1 - 2020/6/23
N2 - 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 39 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.
AB - 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 39 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.
UR - http://www.scopus.com/inward/record.url?scp=85086765451&partnerID=8YFLogxK
U2 - 10.1182/bloodadvances.2020001848
DO - 10.1182/bloodadvances.2020001848
M3 - Article
C2 - 32559291
AN - SCOPUS:85086765451
SN - 2473-9529
VL - 4
SP - 2717
EP - 2722
JO - Blood advances
JF - Blood advances
IS - 12
ER -