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

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

Research output: Contribution to journalArticlepeer-review

Abstract

Genetic lesions that reduce telomerase activity inhibit stem cell replication and cause a range of incurable diseases, including dyskeratosis congenita (DC) and pulmonary fibrosis (PF). Modalities to restore telomerase in stem cells throughout the body remain unclear. Here, we describe small-molecule PAPD5 inhibitors that demonstrate telomere restoration in vitro, in stem cell models, and in vivo. PAPD5 is a non-canonical polymerase that oligoadenylates and destabilizes telomerase RNA component (TERC). We identified BCH001, a specific PAPD5 inhibitor that restored telomerase activity and telomere length in DC patient induced pluripotent stem cells. When human blood stem cells engineered to carry DC-causing PARN mutations were xenotransplanted into immunodeficient mice, oral treatment with a repurposed PAPD5 inhibitor, the dihydroquinolizinone RG7834, rescued TERC 3′ end maturation and telomere length. These findings pave the way for developing systemic telomere therapeutics to counteract stem cell exhaustion in DC, PF, and possibly other aging-related diseases.

Original languageEnglish (US)
Pages (from-to)896-909.e8
JournalCell stem cell
Volume26
Issue number6
DOIs
StatePublished - Jun 4 2020

Keywords

  • PAPD5
  • PARN
  • RG7834
  • TENT4B
  • TERC
  • dihydroquinolizinone
  • high throughput screen
  • telomerase
  • telomeres
  • xenotransplantation

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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