Gene transcription in the cell nucleus is a complex and highly regulated process. Transcription in eukaryotes requires three distinct RNA polymerases, each of which employs its own mechanisms for initiation, elongation, and termination. Termination mechanisms vary considerably, ranging from relatively simple to exceptionally complex. In this review, we describe the present state of knowledge on how each of the three RNA polymerases terminates and how mechanisms are conserved, or vary, from yeast to human.

Many long noncoding RNAs (lncRNAs) are unstable and rapidly degraded in the nucleus by the nuclear exosome. An exosome adaptor complex called NEXT (nuclear exosome targeting) functions to facilitate turnover of some of these lncRNAs. Here we show that knockdown of one NEXT subunit, Mtr4, but neither of the other two subunits, resulted in accumulation of two types of lncRNAs: prematurely terminated RNAs (ptRNAs) and upstream antisense RNAs (uaRNAs). This suggested a NEXT-independent Mtr4 function, and, consistent with this, we isolated a distinct complex containing Mtr4 and the zinc finger protein ZFC3H1. Strikingly, knockdown of either protein not only increased pt/uaRNA levels but also led to their accumulation in the cytoplasm. Furthermore, all pt/uaRNAs examined associated with active ribosomes, but, paradoxically, this correlated with a global reduction in heavy polysomes and overall repression of translation. Our findings highlight a critical role for Mtr4/ZFC3H1 in nuclear surveillance of naturally unstable lncRNAs to prevent their accumulation, transport to the cytoplasm, and resultant disruption of protein synthesis.

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Telomerase is a ribonucleoprotein enzyme that counteracts replicative telomere erosion by adding telomeric sequence repeats onto chromosome ends. Despite its well-established role in telomere synthesis, telomerase has not yet been detected at telomeres. The RNA component of human telomerase (hTR) resides in the nucleoplasmic Cajal bodies (CBs) of interphase cancer cells. Here, in situ hybridization demonstrates that in human HeLa and Hep2 S phase cells, besides accumulating in CBs, hTR specifically concentrates at a few telomeres that also accumulate the TRF1 and TRF2 telomere marker proteins. Surprisingly, telomeres accumulating hTR exhibit a great accessibility for in situ oligonucleotide hybridization without chromatin denaturation, suggesting that they represent a structurally distinct, minor subset of HeLa telomeres. Moreover, we demonstrate that more than 25% of telomeres accumulating hTR colocalize with CBs. Time-lapse fluorescence microscopy demonstrates that CBs moving in the nucleoplasm of S phase cells transiently associate for 10-40 min with telomeres. Our data raise the intriguing possibility that CBs may deliver hTR to telomeres and/or may function in other aspects of telomere maintenance.

Box C/D and H/ACA snoRNAs represent two abundant groups of small noncoding RNAs. The majority of box C/D andH/ACA snoRNAs function as guide RNAs in the site-specific 2′-O-methylation and pseudouridylation of rRNAs, respectively.The box C/D snoRNAs associate with fibrillarin, Nop56, Nop58, and 15.5K/NHPX proteins to form functionalsnoRNP particles, whereas all box H/ACA snoRNAs form complexes with the dyskerin, Nop10, Nhp2, and Gar1 snoRNPproteins. Recent studies demonstrate that the biogenesis of mammalian snoRNPs is a complex process that requires numeroustrans-acting factors. Most vertebrate snoRNAs are posttranscriptionally processed from pre-mRNA introns, and the earlysteps of snoRNP assembly are physically and functionally coupled with the synthesis or splicing of the host pre-mRNA. Thematuring snoRNPs follow a complicated intranuclear trafficking process that is directed by transport factors also involved innucleocytoplasmic RNA transport. The human telomerase RNA (hTR) carries a box H/ACA RNA domain that shares a commonCajal-body-specific localization element with a subclass of box H/ACA RNAs, which direct pseudouridylation ofspliceosomal snRNAs in the Cajal body. However, besides concentrating in Cajal bodies, hTR also accumulates at a small,structurally distinct subset of telomeres during S phase. This suggests that a cell-cycle-dependent, dynamic localization ofhTR to telomeres may play an important regulatory role in human telomere synthesis.