PAPD5

Official Full Name

terminal nucleotidyltransferase 4B

Organism

Homo sapiens

GeneID

64282

Background

Enables guanylyltransferase activity; poly(A) RNA polymerase activity; and telomerase RNA binding activity. Involved in RNA metabolic process; carbohydrate homeostasis; and regulation of nucleobase-containing compound metabolic process. Located in cytosol; nucleolus; and plasma membrane. Part of TRAMP complex. [provided by Alliance of Genome Resources, Feb 2025]

Synonyms

TENT4B; TUT3; PAPD5; TRF4-2;

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Detailed Information

PAPD5 inhibition can restore telomerase activity in patient stem cells

In TBD patients, the recent genetic discoveries of poly(A)-specific ribonuclease (PARN) mutations have been revealed as an enzymatic component of the post-transcriptional machinery responsible for TERC regulation. PARN works as an exoribonuclease for the removal of post-transcriptionally added 3' extension on nascent TERC RNA transcripts to promote maturation and stability of TERC. Conversely, PAPD5 targets transcripts for destruction by recognition and oligo-adenylation of nascent TERC RNA. TERC increase and telomere length restoration in PARN-deficient patient cells can be achieved by PAPD5 knockout.

PAPD5 inhibitors were identified from a high-throughput screen as enhancers of TERC, whose oligoadenylation can be reversed by pharmacologic PAPD5 inhibition. Moreover, TERC increases in human cell lines, primary cells and induced pluripotent stem cells (iPSCs), and CRISPER/Cas9-engineered PARN-deficient primary human hematopoietic stem and progenitor cells (HSPCs) can be also reversed. Few changes of mRNAs and ncRNAs across the transcriptome can be observed even at a sufficient PAPD5 inhibitor level to increase telomere length in patient iPSCs, it may support a potential therapeutic window. Oral administration of PAPD5 inhibitors in human PARN-deficient HSPCs xenotransplanted mice can restore the TERC maturation and telomere elongation. Those findings put forward a validation that PAPD5 works as a promising target to control TERC levels and telomere elongation.

Telomerase activity reduction by the genetic lesions can inhibit stem cell replication and induce a series of incurable diseases, such as dyskeratosis congenita (DC) and pulmonary fibrosis (PF). However, it remains unclear how it works to restore telomerase in stem cells throughout the body. In vitro, in vivo and stem cell models, PAPD5 works as a non-canonical polymerase for the oligoadenylation and destabilization of telomerase RNA component (TERC). PAPD5 inhibition in the immunodeficient mice with xenotransplantation of human blood stem cells engineered to carry DC-causing PARN mutations, more than this, TERC 3' end maturation and telomere length can be rescued. All these findings laid the foundation of systemic telomere therapeutics to offset stem cell exhaustion in DC, PF, and other mighty aging-related diseases.

Figure 1. PAPD5 prolongs the life of the mRNA encoding tumor suppressor TP53 by polyadenylation. (Boele, et al. 2014)

References:

Boele J, Persson H, Shin J W, et al. PAPD5-mediated 3′ adenylation and subsequent degradation of miR-21 is disrupted in proliferative disease. Proceedings of the National Academy of Sciences, 2014, 111(31): 11467-11472.
Nagpal N, Wang J, Zeng J, et al. Small-molecule PAPD5 inhibitors restore telomerase activity in patient stem cells. Cell Stem Cell, 2020, 26(6): 896-909. e8.

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