Basal transcription machinery

This early biological result spurred a variety of biochemical studies of the interactions of various polyamides with the basal transcription machinery and TE-DNA complexes. Two studies have used promoter scanning to identify sites where polyamide binding inhibits transcription [64, 65]. The method uses a series of DNA constructs with designed polyamide binding sites at varying distances from... 

In vitro interactions between HMG proteins and the basal transcription machinery have also been reported. Human HMGBl binds to the TATA-box binding protein (TBP) and interferes with the normal binding of TFIIB in the preinitiation complex [154,155], thereby inhibiting TBP function both HMGBl and TFIIB independently enhance binding of TBP to TATA-box DNA [154]. Similarly, Nhp6ap promotes the formation of a complex with TBP and TFIIA at the TATA... 

The correlation between histone acetylation and eukaryotic transcription were recognized many years ago [128,129]. However, it has not been until very recently, with the discovery that both HATs [130-133] and HDACs [134-138] are an integral part of the basal transcriptional machinery, that the molecular link for this correlation was established. This discovery has rekindled interest in this post-translational histone modification with implications ranging from basic chromatin research to applied medical investigations. Indeed, histone acetylation has been linked to cancer [139-144] and certain types of HDAC inhibitors are already being used to treat certain forms of cancer [145]. 

Nuclear receptors exert their different transcriptional functions through interactions with and the recruitment of co-factors to responsive promoters. Co-factors are either positive or negative regulatory proteins and are classified as co-activators, which promote, or co-repressors, which attenuate the activity of nuclear hormone receptors [46]. The molecular mechanisms that regulate the mutually exclusive interactions of the nuclear receptor with either class of co-factors have been analysed by crystallographic studies. Functional and structural studies have shown that co-activators interact with the transactivation function (AF) of nuclear hormone receptors via short, leucine-rich motifs (LXXLL) termed NR boxes , thereby transducing hormonal signals to the basal transcription machinery [47]. 

Examples of co-activators are the steroid receptor co-activator (SRC) family [48] and the components of the mammalian mediator complex, which possesses chromatin remodelling ability and tethers activated steroid hormone receptors to the basal transcription machinery [49]. Additional co-... 

Kaludov NK, Wolffe AP. MeCP2 driven transcriptional repression in vitro selectivity for methylated DNA, action at a distance and contacts with the basal transcription machinery. Nucleic Acids Res 2000 28 1921-1928. 

We have learnt from the structures that the TBP/TATA complex is a nucleoprotein scaffold upon which other factors, such as TFIIA and TFIIB attach with high affinity through a combination of stereospecific and electrostatic interactions. TFIIB is positioned at the transcriptional start site, between the attachment sites for TBP and Pol II. On the other hand, TFIIA has no contacts with the DNA downstream of the TATA box and does not interact with the transcriptional start site and/or any of the components of the basal transcription machinery, all of which are located downstream of the TATA box. Thus, TFIIA and TFIIB can bind simultaneously, without mutual interference. Moreover, TFIIA is accessible to specific, signal-responsive regulatory transcription factors. Its location upstream of the TATA box also enables TFIIA to absorb and scavenge transcriptional inhibitors, making them ineffectual. 

Fig. 12.9 Indirect control of transcription by cyclin-Cdks involves interactions of transcription fector E2F with the tumour suppressors p53 and pRB. Cyclin D- and cyclin E-associated kinases phosphorylate pRB and lift the biock of transcription. Appropriate changes of the phosphorylation state of p53 improve the specificity of DNA binding arxj promote the transcriptional activity of E2F. This effect is amplified by phosphorylation of p53 by cyiin A-Cdkl. (Cyclin H/Cdk7/CAK and cyclin C/Cdk8 complexes can activate transcription directly, by association with the basal transcription machinery and phosphorylation of RNA polymerase II, Pol II see also Chapters 9 and 10).

Many general repressors function via components of the basal transcription machinery, with the TATA box-binding protein TBP as the major target. Repressors like NC2 are known that bind to the TBP on the promotor and can prevent RNA polymerase II holoenzyme from assembling into the initiation complex. In this way, a general repression of class II genes can be achieved. 

S6]. The phosphorylation does not change the DNA binding properties of CREB but stimulates interaction with the basal transcription machinery. Plant bZIP proteins show similarity to CREB suggesting that an ABF could be regulated in the same way as CREB. 

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