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Transcription Termination by Nuclear RNA Polymerases

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Transcription Termination by Nuclear RNA Polymerases Downloaded from genesdev.cshlp.org on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press REVIEW Transcription termination by nuclear RNA polymerases Patricia Richard and James L. Manley1 Department of Biological Sciences, Columbia University, New York, New York 10027, USA Gene transcription in the cell nucleus is a complex and few base pairs to several kilobases downstream from the highly regulated process. Transcription in eukaryotes 39-end of the mature RNA (Proudfoot 1989). RNAPII requires three distinct RNA polymerases, each of which transcription termination is coupled to 39-end processing employs its own mechanisms for initiation, elongation, of the pre-mRNA (Birse et al. 1998; Hirose and Manley and termination. Termination mechanisms vary consid- 2000; Yonaha and Proudfoot 2000; Proudfoot 2004; erably, ranging from relatively simple to exceptionally Buratowski 2005), and an intact polyadenylation signal complex. In this review, we describe the present state of has long been known to be necessary for transcription knowledge on how each of the three RNA polymerases termination of protein-coding genes in human and yeast terminates and how mechanisms are conserved, or vary, cells (Whitelaw and Proudfoot 1986; Logan et al. 1987; from yeast to human. Connelly and Manley 1988). RNAPIII and RNAPI termination appear simpler than Transcription in eukaryotes is performed by three RNA RNAPII termination. RNAPIII terminates transcription polymerases, which are functionally and structurally at T-rich sequences located a short distance from the related (Cramer et al. 2008). RNA polymerase II (RNAPII) mature RNA 39-end and seems to involve at most a is responsible for transcription of protein-coding genes limited number of auxiliary factors (Cozzarelli et al. and many noncoding RNAs, including spliceosomal 1983). RNAPI terminates at a major terminator located small nuclear RNAs (snRNAs), small nucleolar RNAs downstream from the rRNA precursor sequence and (snoRNAs), microRNA (miRNA) precursors, and cryptic requires terminator recognition by specific protein fac- unstable transcripts (CUTs). RNA polymerase I (RNAPI) tors (Kuhn and Grummt 1989; Lang and Reeder 1995). transcribes the abundant ribosomal RNAs (rRNAs), and Recent studies, though, suggest that additional complex- RNA polymerase III (RNAPIII) transcribes noncoding ities are involved (El Hage et al. 2008; Kawauchi et al. RNAs such as transfer RNAs (tRNAs), 5S rRNA, and 2008). U6 spliceosomal snRNA. Transcription consists of three The three transcription machineries use different strat- main steps: initiation, elongation, and termination, all egies for transcription termination, although they share of which are highly controlled and involve a large number common features (Cramer et al. 2008; Gilmour and Fan of specific factors. While initiation and elongation 2008). This review describes advances in our understand- have been well studied (Sims et al. 2004), termination ing of transcription termination of all three RNAPs, was until recently an obscure mechanism, especially for particularly in human and in yeast, where transcription RNAPII transcription. Termination is crucial for the termination mechanisms are somewhat better character- release of RNAP from its template, and is important ized. We refer the reader to several excellent recent not only to avoid interference with transcription of reviews that have dealt with aspects of transcription downstream genes (Greger et al. 2000), but also to ensure termination (Rosonina et al. 2006; Lykke-Andersen and that a pool of RNAPs is available for reinitiation or Jensen 2007; Gilmour and Fan 2008; Rondon et al. 2008). new transcription. Termination can also prevent forma- We begin with the most complex, RNAPII termination. tion of antisense RNAs that can interfere with normal pre-RNA production, thereby preventing aberrant gene Termination by RNAPII expression. Termination by RNAPII does not occur at a conserved 39-End processing machinery site or constant distance from the 39-end of mature RNAs. In mammals, termination can occur anywhere from a Given the importance of mRNA 39-end formation in transcription termination, we begin with a brief descrip- tion of the 39-end processing reaction and the factors in- [Keywords: Transcription termination; RNA polymerase I; RNA volved. 39-End processing is an essential step in the polymerase II; RNA polymerase III; yeast; mammals] maturation of all mRNAs and is coupled to transcription 1Corresponding author. E-MAIL [email protected]; FAX (212) 865-8246. and splicing, as well as termination (Hirose and Manley 2000; Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1792809. Proudfoot et al. 2002; Buratowski 2005). The mammalian GENES & DEVELOPMENT 23:1247–1269 Ó 2009 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/09; www.genesdev.org 1247 Downloaded from genesdev.cshlp.org on September 23, 2021 - Published by Cold Spring Harbor Laboratory Press Richard and Manley pre-mRNA 39-end processing machinery contains more subunit, Cdc73 or parafibromin, has been identified as than 14 proteins giving rise to a 1-MDa complex (for a tumor suppressor protein, and the Paf1 protein is over- review, see Colgan and Manley 1997; Zhao et al. 1999; expressed in many cancers (Chaudhary et al. 2007). Mandel et al. 2008; see also Shi et al. 2009). In yeast, noncanonical nuclear PAPs, Trf4/5 (Haracska In mammals, cleavage and polyadenylation occur et al. 2005; Egecioglu et al. 2006; Houseley and Tollervey ;10–30 nucleotides (nt) downstream from a conserved 2006), function in a nuclear RNA surveillance pathway hexanucleotide, AAUAAA, and ;30 nt upstream of a less as part of the TRAMP (Trf–Air–Mtr4 polyadenylation) conserved U- or GU-rich region. The AAUAAA signal is complex, which activates degradation by the exosome of recognized by the cleavage and polyadenylation specific- a variety of aberrant nuclear precursors of many types of ity factor (CPSF), which contains five subunits: CPSF-30, RNAs after addition of a poly(A) tail (LaCava et al. 2005). CPSF-73, CPSF-100, CPSF-160, and Fip1. Cleavage stim- Although not well studied, this RNA surveillance function ulation factor (CstF) contains three subunits—CstF-50, is likely conserved in humans since homologs of the CstF-77, and CstF-64—the latter of which directly recog- TRAMP and exosome complexes are present in mammals. nizes the U/GU-rich element. The endonucleolytic cleav- age that precedes polyadenylation is carried out by CTD of the RNAPII large subunit CPSF-73 (Ryan et al. 2004; Mandel et al. 2006). CPSF-73 contains a metallo-b-lactamase domain and is a member At least in mammals, the CTD plays an important role in of the b-CASP protein superfamily (Callebaut et al. 2002). 39-end processing as first determined by experiments CPSF-73 is also likely responsible for cleavage of non- examining the effects on processing of CTD deletions in polyadenylated histone pre-mRNAs (Marzluff et al. 2008; transfected cells (McCracken et al. 1997) and the re- Yang et al. 2009). CPSF-100 also belongs to the b-CASP quirement of the CTD for efficient 39 cleavage in vitro superfamily (Callebaut et al. 2002) but lacks certain key (Hirose and Manley 1998). The CTD of RNAPII is flexibly catalytic residues and plays an unknown role in 39-end linked to the core enzyme and consists of heptapeptide cleavage. However, mutations affecting the metallo- repeats (25 or 26 repeats in yeast, 52 in mammals) with b-lactamase domain of both CPSF-73 and CPSF-100 the consensus sequence Tyr1–Ser2–Pro3–Thr4–Ser5– impair the endonucleolytic cleavage of histone mRNA Pro6–Ser7 (YSPTSPS). The CTD displays different precursors (Kolev et al. 2008). CPSF-160, which directly phosphorylation patterns during the transcription cycle recognizes AAUAAA, binds CPSF-100, CstF-77, poly(A) (Phatnani and Greenleaf 2006; Egloff and Murphy polymerase (PAP), and Fip1 (Murthy and Manley 2008). RNAPII is recruited to the promoter in an unphos- 1995; Kaufmann et al. 2004). In addition, the cleavage phorylated form (RNAPIIA) that becomes extensively complex contains CFI (cleavage factor I), a dimeric pro- phosphorylated during transcription (RNAPIIO). Phos- tein implicated in the regulation of poly(A) site selec- phorylation of Ser5 by the cyclin-dependant kinase tion (Ruegsegger et al. 1998; Brown and Gilmartin 2003; CDK7, a subunit of the general transcription factor Venkataraman et al. 2005), and CFII, containing Pcf11 and TFIIH, occurs at the initiation step of transcription to Clp1. Clp1, which interacts with the CFI and CPSF facilitate promoter release and recruitment of capping complexes (de Vries et al. 2000), also possesses an RNA factors (Komarnitsky et al. 2000; Schroeder et al. 2000) kinase activity (Weitzer and Martinez 2007), although the and the methyltransferase Set1 that is responsible for significance of this to 39-end formation is unknown. trimethylation of Lys4 on histone 3 (H3-K4) (Hampsey Another protein, symplekin, is also part of the 39-end and Reinberg 2003). Phosphorylation of Ser2 by the processing complex and appears to function as a scaffold positive transcription elongation factor P-TEFb, compris- (Takagaki and Manley 2000). PABP [poly(A)-binding pro- ing the kinase CDK9 (Ctk1 in yeast) and cyclin T, occurs tein] protects the pre-mRNA from exonuclease degrada- after initiation. Ser2 phosphorylated CTD helps to recruit tion by binding the poly(A) tail and is required for correct and/or stabilize polyadenylation factors, thereby facili- and efficient poly(A) tail synthesis (Minvielle-Sebastia tating coupling of transcription and mRNA 39-end for- et al. 1997). mation. For instance, in yeast, Ser2 phosphorylation of Several factors help link 39-end processing to transcrip- the CTD potentiates interaction with the essential poly- tion. For example, the C-terminal domain (CTD) of the adenylation factor Pcf11 (de Vries et al. 2000; Barilla et al. RNAPII largest subunit also plays an important role in 2001; Licatalosi et al. 2002; Ahn et al. 2004). The H3-K36 39-end processing, likely by mediating interactions with methyltransferase Set2 binds elongating RNAPII, recog- 39-end processing factors (McCracken et al.
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