Role of RNA Biogenesis Factors in the Processing and Transport of Human Telomerase RNA

Abstract

Telomerase RNA has long been considered to be a noncoding component of telomerase. However, the expression of the telomerase RNA gene is not always associated with telomerase activity. The existence of distinct TERC gene expression products possessing different functions were demonstrated recently. During biogenesis, hTR is processed by distinct pathways and localized in different cell compartments, depending on whether it functions as a telomerase complex component or facilitates antistress activities as a noncoding RNA, in which case it is either processed in the mitochondria or translated. In order to identify the factors responsible for the appearance and localization of the exact isoform of hTR, we investigated the roles of the factors regulating transcription DSIF (Spt5) and NELF-E; exosome-attracting factors ZCCHC7, ZCCHC8, and ZFC3H1; ARS2, which attracts processing and transport factors; and transport factor PHAX during the biogenesis of hTR. The data obtained revealed that ZFC3H1 participates in hTR biogenesis via pathways related to the polyadenylated RNA degradation mechanism. The data revealed essential differences that are important for understanding hTR biogenesis and that are interesting for further investigations of new, therapeutically significant targets.

How Structural Features Define Biogenesis and Function of Human Telomerase RNA Primary Transcript

“…The depletion of PABPN1 (poly(A)-binding protein nuclear 1) results in a decreased level of total hTERC , which is rescued when NEXT exosome components are co-depleted [ 18 , 26 ]. The depletion of the PAXT (poly(A) tail exosome targeting) complex involved in the degradation of polyadenylated RNAs through interaction with PABPN1 results in the accumulation of the unprocessed 3′-extended form of hTERC [ 26 , 27 ]. Polyadenylation is necessary for processing hTERC to the mature component of the telomerase complex.…”

“…It has recently been demonstrated [ 27 ] that PHAX deficiency does not influence the level of mature hTERC . The co-depletion of the PAXT complex decreased the amount of mature and 3′-extended hTERC transcripts, and the co-depletion of TRAMP stimulated the accumulation of 3′-extended hTR transcripts, especially in the cytoplasmic fraction.…”

“…ARS2 substitutes NELF and coordinates the distinct, mutually exclusive complex assembly to process the primary transcript [ 29 , 30 , 31 , 32 ]. During processing, monomethylated (MMG), polyadenylated hTERP mRNA is protected by PABPN1, which is substituted by PABP and exported to the cytoplasm, where it is translated [ 18 , 27 ]. Oligoadenylated hTERC transcripts may be degraded by RNA exosomes attracted by the PAXT complex [ 27 ], or may be trimmed by PARN followed by degradation through NEXT-attracted RNA-exosomes [ 21 ], or transported by PHAX to the nucleolus [ 28 ] where it is hypermethylated (TMG) by TGS1 [ 16 ] and matured by TRAMP-mediated RNA exosome trimming [ 15 , 18 ] for assembly into the active telomerase complex.…”

“…Notably, the total level of hTERC transcript was increased in TGS1-depleted cells, without the redistribution of portions of 3′-end-extended and oligoadenylated forms of hTERC [16]. Integrator (Int), DSIF, NELF, and cap-binding complex (CBC) assist RNA polymerase II to synthesize the primary hTERC transcript [14,27]. ARS2 substitutes NELF and coordinates the distinct, mutually exclusive complex assembly to process the primary transcript [29][30][31][32].…”

“…Oligoadenylated hTERC transcripts may be degraded by RNA exosomes attracted by the PAXT complex [27], or may be trimmed by PARN followed by degradation through NEXT-attracted RNA-exosomes [21], or transported by PHAX to the nucleolus [28] where it is hypermethylated (TMG) by TGS1 [16] and matured by TRAMP-mediated RNA exosome trimming [15,18] for assembly into the active telomerase complex. NELF, and cap-binding complex (CBC) assist RNA polymerase II to synthesize the primary hTERC transcript [14,27]. ARS2 substitutes NELF and coordinates the distinct, mutually exclusive complex assembly to process the primary transcript [29][30][31][32].…”