Chromatin-modifying complexes

Hassan AH, Prochasson P, Neely KE, Galasinski SC, Chandy M, Carrozza MJ, Workman JL (2002) Function and selectivity of bromodomains in anchoring chromatin-modifying complexes to promoter nucleosomes. Cell 111 369-379... 

Chromatin-modifying complexes are classified into two major groups (1) enzymes that conttol covalent modifications of the amino-terminal tails of histones (acetylation, methylation, phosphorylation, ubiquitinylation) (see Sections 1.3 and... 

It is assumed that trans-activating domains are structural elements that can adapt to become complementary to a surface of the transcription apparatus in a flexible and rather unspecific manner. Furthermore, parts of the trans-activating domain mediate contacts to the chromatin-remodeling and chromatin-modifying complexes and recruit these to the enhancer or promotor region. Information on the structure of... 

Chromatin is composed of nucleosomes, where each comprise 147 base pairs of DNA wrapped around an octamer oftwo copies of each histone H2A, H2B, H3, and H4. Nucleosomes are folded into higher-order structures that are stabilized by linker histones. Chromatin structure can be altered by enzymes that posttranslationally modify histones (e.g., through phosphorylation, acetylation, methylation, or ubiquitination) or by ATP-driven chromatin-remodeling complexes that alter nucleosome position and/or composition. 

Like HATs, most functional HDACs are embedded in large multifunctional protein complexes, which also contain other chromatin modifying enzymes and coregulator proteins [1]. 

In the case of liganded NRs, ligand binding is the first and ciucial molecular event that switches the function of these transcription factors from inactive to active state by inducing a conformational change in the LBD of the receptor (Fig. 1). This specific conformation allows the second step of NR activation that corresponds to the recruitment of coregulatoiy complexes, which contain chromatin-modifying enzymes required for transcription. The transcriptional coactivators are very diverse and have expanded to more than hundred in number. These include the pi 60 family of proteins,... 

Kornberg, R.D. and Lorch, Y. (1999) Chromatin-modifying and -remodeling complexes. Curr. Opin. Genet. Dev. 9, 148-151. 

The amount of information is still insufficient to predict how packaging of DNA in chromatin modifies the final product distribution in DNA. If the stable end products reflect a doubling in reductive damage while oxidative damage remains the same, then one would expect an increase in frequency and complexity of clustered lesions. If that proves true, the histone proteins and attending nucleosomes structure would act as radiation sensitizers. 

Ogawa H, Ishiguro K, Gaubatz S, Livingston DM, Nakatani Y. A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in GO cells. Science 2002 296 1132-1136. 

Baetz KK, et al. The ctfl3-30/CTF13 genomic haploinsuffi-ciency modifier screen identifies the yeast chromatin remodeling complex RSC, which is required for the establishment of sister chromatid cohesion. Mol. Cell. Biol. 2004 24 1232-1244. 

Much remains to be learned about the structure of chromatin and how that structure influences transcription. What directs certain regions of chromatin to form heterochromatin where transcription is repressed Precisely how Is the structure of chromatin changed by activators and repressors and how does this promote or inhibit transcription Once chromatin-remodeling complexes and histone acetylase complexes become associated with a promoter region, how do they remain associated Do certain subunits of these complexes associate with modified histone tails so that additional complexes associate along the length of a chromatin fiber as additional histones are modified ... 

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