Small-Molecule PAPD5 Inhibitors Restore Telomerase Activity in Patient Stem Cells

Nagpal, Neha; Wang, Jianing; Zeng, Jing; Lo, Emily K.W.; Moon, Diane H.; Luk, Kevin; Braun, Roman Othmar; Burroughs, Lauri M.; Keel, Siobán; Reilly, Christopher R.; Lindsley, R. Coleman; Wolfe, Scot A.; Tai, Albert; Cahan, Patrick; Bauer, Daniel E.; Fong, Yick W.; Agarwal, Suneet

doi:10.1016/j.stem.2020.03.016

Cited by 74 publications

(73 citation statements)

References 91 publications

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“…RG7834 treatment was sufficient to restore the in vitro definitive hematopoietic development of DKC1_A353V hESCs, similarly to what we have recently observed with the genetic silencing of PAPD5. 18 Although these experiments represent the first nongenetic rescue of hematopoietic development from hESCs in DKC1 mutant cells, it has recently been shown that PAPD5 inhibitors are able to promote telomere restoration in different patient-derived DC samples in vitro and in vivo, through xenotransplantation assays 27 ;…”

Section: Resultsmentioning

confidence: 99%

Chemical inhibition of PAPD5/7 rescues telomerase function and hematopoiesis in dyskeratosis congenita

Shukla

Jeong²,

Sturgeon

et al. 2020

Blood Advances

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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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Section: Resultsmentioning

confidence: 99%

Chemical inhibition of PAPD5/7 rescues telomerase function and hematopoiesis in dyskeratosis congenita

Shukla

Jeong²,

Sturgeon

et al. 2020

Blood Advances

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“…104 In terms of tolerability, PAPD5 null human cell lines and pluripotent stem cells are able to be isolated and propagated indefinitely, and show decreased TERC oligo-adenylation and increased TERC levels. 102,114 These observations provide the basis for considering PAPD5 a "druggable" target to restore TERC and telomere length in certain forms of DC/TBDs 100 ( Figure 2B).…”

Section: Therapeutic Potential Of Modulating Terc Processingmentioning

confidence: 95%

“…As described above, several studies have demonstrated that genetic inhibition of PAPD5 can restore TERC levels in PARN-or dyskerin-deficient states. 96,[98][99][100]102,104,114 Stable long-term shRNA-mediated PAPD5 depletion is tolerated in PARN-mutant patient iPSCs and restores TERC levels, telomerase activity and telomere length 100 ( Figure 2B).…”

Section: Therapeutic Potential Of Modulating Terc Processingmentioning

confidence: 99%

“…Recently a high-throughput enzymatic screen identified novel and specific PAPD5 small molecule inhibitors that restored telomerase activity in DC patients' iPSCs. 114 One such PAPD5 inhibitor, a quinoline called BCH001, showed the capacity to increase TERC maturation and RNA levels and elongate telomeres in PARN-mutant patient stem cells ( Figure 2B). Importantly, telomere elongation by BCH001 in patient cells was dependent on TERT, expressed either endogenously in iPSCs or ectopically in fibroblasts.…”

Section: Therapeutic Potential Of Modulating Terc Processingmentioning

confidence: 99%

“…115,116 DHQ molecules increase TERC and telomere length in DC patient iPSCs in vitro. 114 In an in vivo mouse…”

Section: Therapeutic Potential Of Modulating Terc Processingmentioning

confidence: 99%

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Telomerase RNA processing: Implications for human health and disease

Nagpal

Agarwal

2020

Stem Cells

Self Cite

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Telomeres are composed of repetitive DNA sequences that are replenished by the enzyme telomerase to maintain the self-renewal capacity of stem cells. The RNA component of human telomerase (TERC) is the essential template for repeat addition by the telomerase reverse transcriptase (TERT), and also serves as a scaffold for several factors comprising the telomerase ribonucleoprotein (RNP). Unique features of TERC regulation and function have been informed not only through biochemical studies but also through human genetics. Disease-causing mutations impact TERC biogenesis at several levels including RNA transcription, posttranscriptional processing, folding, RNP assembly, and trafficking. Defects in TERC reduce telomerase activity and impair telomere maintenance, thereby causing a spectrum of degenerative diseases called telomere biology disorders (TBDs). Deciphering mechanisms of TERC dysregulation have led to a broader understanding of noncoding RNA biology, and more recently points to new therapeutic strategies for TBDs. In this review, we summarize over two decades of work revealing mechanisms of human telomerase RNA biogenesis, and how its disruption causes human diseases.

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The S‐adenosylmethionine analog sinefungin inhibits the trimethylguanosine synthase TGS1 to promote telomerase activity and telomere lengthening

et al. 2021

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Mutations in many genes that control the expression, the function, or the stability of telomerase cause telomere biology disorders (TBDs), such as dyskeratosis congenita, pulmonary fibrosis, and aplastic anemia. Mutations in a subset of the genes associated with TBDs cause reductions of the telomerase RNA moiety hTR, thus limiting telomerase activity. We have recently found that loss of the trimethylguanosine synthase TGS1 increases both hTR abundance and telomerase activity and leads to telomere elongation. Here, we show that treatment with the S-adenosylmethionine analog sinefungin inhibits TGS1 activity, increases the hTR levels, and promotes telomere lengthening in different cell types. Our results hold promise for restoring telomere length in stem and progenitor cells from TBD patients with reduced hTR levels.

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Small-Molecule PAPD5 Inhibitors Restore Telomerase Activity in Patient Stem Cells

Cited by 74 publications

References 91 publications

Chemical inhibition of PAPD5/7 rescues telomerase function and hematopoiesis in dyskeratosis congenita

Chemical inhibition of PAPD5/7 rescues telomerase function and hematopoiesis in dyskeratosis congenita

Telomerase RNA processing: Implications for human health and disease

The S‐adenosylmethionine analog sinefungin inhibits the trimethylguanosine synthase TGS1 to promote telomerase activity and telomere lengthening

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