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- RNA polymerase II and the integration of nuclear events

RNA polymerase II and the integration of nuclear events

Yutaka Hirose,2 and James L. Manley1

1 Department of Biological Sciences, Columbia University, New York, New York 10027 USA; 2 Department of Molecular and Cellular Biology, Cancer Research Institute, Kanazawa University, Ishikawa 920-0934, Japan

Genes and Development, Vol. 14, No. 12, pp. 1415-1429, June 2000

The synthesis of a messenger RNA in the nucleus of a eukaryotic cell is an immensely complex undertaking. Each step in the pathway requires an enormous number of protein factors and identifying them and figuring out how they work has been a major goal of molecular biologists for the last two decades. Based on in vitro assays showing that each of the major steps, that is, transcription, capping, splicing, and polyadenylation, can be carried out in isolation, and because intuitively each of these reactions seemed quite distinct from the others, it had been widely assumed that the machinery responsible for each step was distinct and functioned essentially independently. However, numerous studies during the last few years have provided considerable evidence that this is not the case. In retrospect, this conclusion had been foreshadowed by earlier experiments pointing to the possibility that any one of these reactions could enhance some aspect of another. For example, evidence was presented consistent with the idea that the mRNA 5' cap could play a role in allowing efficient transcription (Jove and Manley 1982), splicing (Edery and Sonenberg 1985), and even polyadenylation (Hart et al. 1985). Subsequently, it was shown in several labs that an intact polyadenylation signal could be required for transcription termination by RNA polymerase II (RNAP II) (Whitelaw and Proudfoot 1986; Logan et al. 1987; Connelly and Manley 1988), and that the presence of splicing signals on a pre-mRNA could enhance polyadenylation and vice versa (Niwa et al. 1990; Niwa and Berget 1991). However, none of these interactions really suggested just how intimate these associations might be, especially the emergence of RNAP II as an important component of all these reactions: capping, splicing, polyadenylation, as well as of course transcription.

The largest subunit of RNAP II has a unique domain, not related to regions in any known protein, at its carboxyl terminus, termed the carboxy-terminal domain (CTD). The CTD consists of multiple repeats of an evolutionary conserved heptapeptide with the consensus sequence Tyr-Ser-Pro-Thr-Ser-Pro-Ser (for review, see Corden 1990). The number of the repeats varies among different organisms, ranging from 26-27 in yeast to 52 in mammals. In metazoans, there can be significant degeneracy at some positions in the CTD, in mammals this is most apparent in the most carboxy-terminal repeats. The significance of this degeneracy is currently unknown. The CTD is rich in potential phosphoacceptor amino acid residues and, in keeping with this, is subject to reversible phosphorylation during the transcription cycle (for review, see Dahmus 1996). RNAP II with a hypophosphorylated CTD (RNAP IIA) is included preferentially in the transcription preinitiation complex formed at the promoter, whereas RNAP II with a hyperphosphorylated CTD (RNAP IIO) is associated with elongation complexes. Not unexpectedly, the CTD plays an important role in transcription, especially transcription initiation (for review, see Carlson 1997).

In this review, we discuss recent progress relating to what might be called the integration of nuclear events. Our focus will be on studies aimed at deciphering how RNAP II functions in the various RNA processing reactions needed to synthesize a mature mRNA. Much of what we will discuss is illustrated in the model shown in Figure 1. The reader is also referred to several excellent related reviews that have appeared recently (Neugebauer and Roth 1997; Steinmetz 1997; Bentley 1999; Minvielle-Sebastian and Keller 1999).

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