title: Posttranscriptional manipulation of TERC reverses molecular hallmarks of telomere disease.
abstract: The telomerase RNA component (TERC) is a critical determinant of cellular self-renewal. Poly(A)-specific ribonuclease (PARN) is required for posttranscriptional maturation of TERC. PARN mutations lead to incomplete 3' end processing and increased destruction of nascent TERC RNA transcripts, resulting in telomerase deficiency and telomere diseases. Here, we determined that overexpression of TERC increased telomere length in PARN-deficient cells and hypothesized that decreasing posttranscriptional 3' oligo-adenylation of TERC would counteract the deleterious effects of PARN mutations. Inhibition of the noncanonical poly(A) polymerase PAP-associated domain-containing 5 (PAPD5) increased TERC levels in PARN-mutant patient cells. PAPD5 inhibition was also associated with increases in TERC stability, telomerase activity, and telomere elongation. Our results demonstrate that manipulating posttranscriptional regulatory pathways may be a potential strategy to reverse the molecular hallmarks of telomere disease.
authors.forename: Baris
authors.initials: B
authors.lastname: Boyraz
authors.forename: Diane H
authors.initials: DH
authors.lastname: Moon
authors.forename: Matthew
authors.initials: M
authors.lastname: Segal
authors.forename: Maud Z
authors.initials: MZ
authors.lastname: Muosieyiri
authors.forename: Asli
authors.initials: A
authors.lastname: Aykanat
authors.forename: Albert K
authors.initials: AK
authors.lastname: Tai
authors.forename: Patrick
authors.initials: P
authors.lastname: Cahan
authors.forename: Suneet
authors.initials: S
authors.lastname: Agarwal
mesh_terms: D018076:DNA, Complementary / Q000378:metabolism; D019871:Dyskeratosis Congenita / Q000235:genetics; D005095:Exoribonucleases / Q000235:genetics*; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D009154:Mutation; D010641:Phenotype; D011499:Protein Processing, Post-Translational; D012313:RNA / Q000235:genetics*; D034622:RNA Interference; D012316:RNA Nucleotidyltransferases / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012867:Skin / Q000378:metabolism; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D016615:Telomere / Q000648:ultrastructure
chemical_list: D018076:DNA, Complementary; D005095:Exoribonucleases; D012313:RNA; D012316:RNA Nucleotidyltransferases; D034741:RNA, Small Interfering; D019098:Telomerase; C422952:telomerase RNA; C567954:TENT4B protein, human