Human telomerase RNA and box H/ACA scaRNAs share a common Cajal body–specific localization signal

Abstract

Telomerase is a ribonucleoprotein reverse transcriptase that uses its RNA component as a template for synthesis of telomeric DNA repeats at the ends of linear eukaryotic chromosomes. Here, fluorescence in situ hybridization demonstrates that in HeLa cancer cells, human telomerase RNA (hTR) accumulates in the nucleoplasmic Cajal bodies (CBs). Localization of transiently expressed hTR to CBs is supported by a short sequence motif (411-UGAG-414) that is located in the 3′-terminal box H/ACA RNA-like domain of hTR and that is structurally and functionally indistinguishable from the CB-specific localization signal of box H/ACA small CB-specific RNAs. In synchronized HeLa cells, hTR shows the most efficient accumulation in CBs during S phase, when telomeres are most likely synthesized. CBs may function in post-transcriptional maturation (e.g., cap hypermethylation of hTR), but they may also play a role in the assembly and/or function of telomerase holoenzyme.

Coilin: The first 25 years

“…43 Telomerase RNA is retained in CBs via protein WRAP53, which binds the CAB box sequence found in telomerase RNA and many scaRNAs. 39,[44][45][46][47] WRAP53 interacts with coilin, providing the mechanistic link between telomerase and coilin. 48,49 Telomerase RNA localization to CBs was suggested to be important for telomerase function and mislocalization of telomerase RNA from CBs correlates with reduced telomerase activity.…”

“…Early experiments detected telomerase RNA in CBs, and CBs associate with telomerase during Sphase. [38][39][40][41][42] Interestingly, telomerase RNA localization to CBs seems to be humanspecific because telomerase RNA was not found in mouse CBs. 43 Telomerase RNA is retained in CBs via protein WRAP53, which binds the CAB box sequence found in telomerase RNA and many scaRNAs.…”

Evolutionary patterns of non-coding RNAs

“…The vertebrate telomerase RNA apparently has co-opted a H/ACA box snoRNA domain [284] during its evolution, shares evolutionarily conserved proteins with H/ACA snoRNPs, and contains a Cajal body specific localization signal that is shares with a Cajal body specific subclass of H/ACA snoRNPs [181].…”

TCAB1: Driving telomerase to Cajal bodies

“…1B), is bound by dyskerin, and localizes to Cajal bodies. 8,9 Dyskerin plays a central role in the assembly and stability of all H/ACA RNPs, including telomerase. In settings of impaired dyskerin function, levels of TERC and telomerase are reduced, leading to telomere shortening.…”

“…In humans, the localization of telomerase to Cajal bodies is critical for telomere maintenance, since point mutation in TERC's CAB box or knockdown of TCAB1 results in TERC mislocalization and inefficient telomere synthesis by telomerase. 8,21,22 From the growing list of noncoding RNAs and their dedicated assembly pathways, why did telomerase adopt the scaRNA pathway? What do Cajal bodies contribute to telomerase function?…”