Corepressor pathways

Fig. 4. Domain structure of mammalian DNA methyltransferases. (a) The domain structure of the known DNA methyltransferases, depicting the conserved catalytic domain (dark box) and other identified domains. Conserved aminoacid motifs in the catalytic domain are shown in lighter shade of gray. (b) Schematic representation of the reported protein-protein interactions of Dnmtl with a number of regulatory proteins interactions that modulate Dnmtl methyitransferase activity (darker rectangles) or mediate methylation-independent transcriptional repression mechanisms (lighter rectangles). When Dnmtl represses transcription through its enzymatic activity, it has been described to interact with some proteins PCNA [37] and an oncogenic transcription factor PML-RAR [25]. Note that in the case of the PML-RAR transcription factor, histone deacetylase 1 (HDACl) is also bound to the complex. When Dnmtl represses transcription via methylation-independent pathways, it binds to HDACs either directly [34] or indirectly through other proteins the corepressor DMAPl [33], the retinoblastoma protein, and a gene-specific transcription factor [31].

Several aaRS-like proteins are involved in metabobc pathways (1). For example, E. coli asparagine synthase, an aspartyl-tRNA synthetase (AspRS)-like enzyme, catalyzes the synthesis of asparagine from aspartate and ATP. A paralog of LysRS-II, called PoxA/GenX, is important for pyruvate oxidase activity in E. coli and Salmonella typhimurium and for virulence in S. typhimurium. The E. coli biotin synthetase/repressor protein (BirA), which has a domain that resembles structurally the seryl-tRNA synthetase (SerRS) catalytic domain, activates biotin to modify posttranslationaUy various metabolic proteins involved in carboxylation and decarboxylation. BirA can also bind DNA and regulate its own transcription using biotin as a corepressor. A histidyl-tRNA synthetase (HisRS)-hke protein from Lactococcus lactis, HisZ is involved in the allosteric activation of the phosphoribosyl-transferase reaction. 

Huang EY, Zhang J, Miska EA, Guenther MG, Kouzarides T, Lazar MA. 2000. Nuclear receptor corepressors partner with class II histone deacetylases in a Sin3-independent repression pathway. Genes Dev. 14 45-54... 

In summary, transcriptional activation mediated by RAR-RXR complexes is a complex, multistep process that is not entirely understood at the molecular level. However, it is clear that agonist-induced, RAR-RXR conformational change, which is crucial for dissociation of the corepressor complex and induction of a receptor conformation that facilitates interaction of the receptor with two distinct classes of coactivator proteins, the HAT and TRAP proteins, plays a central role in the signaling pathways of RAR-RXR complexes leading to transcriptional activation. 

Blaschke, F., Takata, Y., Caglayan, E., Collins, A.,Tontonoz, P., Hsueh, W.A. and Tangirala, R.K. (2006) A nuclear receptor corepressor-dependent pathway mediates suppression of cytokine-induced C-reactive protein gene expression by liver X receptor. Circulation Research, 99, e88-e99. 

In an inducible enzyme system, the R. is inactive in the presence of the effector (inducer) binding to the inducer apparently changes the conformation of the R., so that it no longer binds to the operator (see Enzyme induction). Synthesis of mRNA can therefore proceed only when the inducer is present. In enzyme repression, the situation is revets R. is activated by a corepressor (the endproduct of a biosynthetic pathway, e.g. an amino acid) so that it can bind to the operator. In this case, synthesis of mRNA proceeds only in the absence of corepressor (see Enzyme repression). See also Derepression. 

Sanyal S, Bavner A, Haroniti A, Nilsson LM, Lundasen T, Rehnmark S, Witt MR, Einarsson C, Talianidis I, Gustafsson JA, Treuter E (2007) Involvement of corepressor complex subunit GPS2 in transcriptional pathways governing human bile acid biosynthesis. Proc Natl Acad Sci U S A 104 15665-15670... 

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