Posttranscriptional manipulation of TERC reverses molecular hallmarks of telomere disease

PARN and TOE1 Constitute a 3′ End Maturation Module for Nuclear Non-coding RNAs

“…Tailing in this quality control process is mediated by the Trf4/5-Air1/2-Mtr4 polyadenylation (TRAMP) complex (LaCava et al, 2005;Vaná cová et al, 2005;Wyers et al, 2005). Previous studies revealed that the human TRAMP complex competes with PARN, leading to the destabilization of premature RNAs in the absence of PARN (Boyraz et al, 2016;Moon et al, 2015;Nguyen et al, 2015;Shukla et al, 2016;Tseng et al, 2015). To investigate whether TOE1 also competes with the TRAMP complex, we selected RNAs with significant changes in the 3 0 end profile from RNA sequencing (RNA-seq) data ( Figure S3A), and we assessed changes in RNA processing and stability by northern blotting ( Figure 3A).…”

“…PARN also functions to promote the maturation of ncRNAs, which include small nucleolar RNAs (snoRNAs); small Cajal body-specific RNAs (scaRNAs); and telomerase RNA component (TERC), Y RNAs, and microRNA-451 (Berndt et al, 2012;Boyraz et al, 2016;Dhanraj et al, 2015;Moon et al, 2015;Nguyen et al, 2015;Shukla and Parker, 2017;Shukla et al, 2016;Tseng et al, 2015;Yoda et al, 2013). The precursors of these RNAs have 3 0 extensions that are trimmed by exonucleases (Kiss et al, 2006;Matera et al, 2007;Schmidt and Cech, 2015).…”

“…The precursors of these RNAs have 3 0 extensions that are trimmed by exonucleases (Kiss et al, 2006;Matera et al, 2007;Schmidt and Cech, 2015). In the middle of the trimming process, an adenosine tail is often added to processing intermediates, and PARN targets the oligo(A) tail not only to remove it but also to finalize the 3 0 end formation (Berndt et al, 2012;Boyraz et al, 2016;Moon et al, 2015;Nguyen et al, 2015;Shukla et al, 2016;Tseng et al, 2015). This exonucleolytic activity of PARN is required for the stable expression of TERC, and a deficiency in PARN causes telomere-related congenital disorders, such as bone marrow failure and pulmonary fibrosis (Boyraz et al, 2016;Burris et al, 2016;Dhanraj et al, 2015;Kropski et al, 2017;Petrovski et al, 2017;Stuart et al, 2015;Tummala et al, 2015).…”

“…Most of the functional studies on PARN or TOE1 have relied on in vitro or in vivo reporter assays (Cevher et al, 2010;Copeland and Wormington, 2001;Gherzi et al, 2004;Kim and Richter, 2006;Kö rner et al, 1998;Lai et al, 2003;Lejeune et al, 2003;Lin et al, 2007;Miller and Gomez-Cambronero, 2017;Moraes et al, 2006;Wagner et al, 2007;Yamashita et al, 2005;. Some recent studies have employed deep sequencing (Berndt et al, 2012;Boyraz et al, 2016;Lardelli et al, 2017;Moon et al, 2015;Nguyen et al, 2015;Shukla and Parker, 2017;Shukla et al, 2016;Tseng et al, 2015), but these analyses were restricted to specific RNA species. These methods did not provide a comprehensive perspective on the activity of these enzymes.…”

How RNAi machinery enters the world of telomerase

“…These long forms are predominantly degraded by the nuclear exosome targeting complex (NEXT), and the exosome [49,50]. Moreover, TERC undergoes a cycle of oligoadenylation mediated by PAPD5 (poly(A) polymerase PAP-associated domain-containing 5), a non-canonical poly-A polymerase that is a component of the nuclear polyadenylation complex TRAMP [51,52]. Since TERC oligoadenylated isoforms are degraded by the exosome, the Poly(A)-specific ribonuclease (PARN) antagonizes degradation by removing oligo (A) tails from TERC [53][54][55].…”