Chromatin protein effect

The role of PARP-1 as a modulator of chromatin stiucture, as well as its chromatin-dependent effects on transcription, has been well established in the literature (D Amours et al, 1999 Kraus and Lis, 2003 Rouleau et al, 2004 Kim et al, 2005). In this section, we will highlight some of the historical studies, as well as more recent studies, that have characterized the role of PARP-1 and PAR in these processes. Note that, when describing this work, the term PARP in the absence of any additional identifiers refers to PAR-generating proteins of ambiguous identity (e.g., as in early studies, which were conducted without the knowledge that multiple PARP family members exist, or when multiple splice variants of a PARP-1-like protein exist in a single organism, as in Drosophila). 

Reuter G, Spierer P (1992) Position effect variegation and chromatin proteins. Bioessays 14 605—612 Rice JC, Briggs SD, Ueberheide B, Barber CM, Shabanowitz J, Hunt DF, Shinkai Y, Allis CD (2003) Histone methyltransferases direct different degrees of methylation to define distinct chromatin domains. Mol Cell 12 1591-1598... 

These brief treatments of diverse osmotic effects on DNA are adequate to show that changes in the solute composition of the nucleoplasm and cytoplasm trigger a substantial number of effects on the structure and function of DNA and chromatin. These effects, which may be lethal if not reversed, are paired with regulatory responses that lead to changes in the amounts and activities of a wide range of enzymatic, transport, and gene regulatory proteins,... 

Dorn, R. et al. (1993). The enhancer of position-effect variegation of Drosophila, E(var) 3-93D, codes for a chromatin protein containing a conserved domain common to several transcriptional regulators. Proc. Natl. Acad. Sci. USA 90(23), 11376-11380. 

These observations regarding DNA strand-breaks are at most, suggestive that perhaps the molecular mechanism of ADPRT action in cell differentiation involves breakage and rejoining of DNA. However, other mechanisms are very plausible. For example, ADP-ribosylation may be required because of its effect on chromatin conformation, or specific regulatory chromatin proteins may be ADP-ribosylated as a signal for the induction of a previously non-expressed gene. 

Kun E, Romaschin AD, Blasdell RJ, Jackowski G (1981) ADP-ribosylation of nonhistone chromatin proteins in vivo and of actin in vitro and effects of normal and abnormal growth conditions and organ-specific hormonal influences. In Holzer H (ed) Proceedings of the international Titisee conference on metabolic interconversion of regulatory enzymes. Springer, Berlin Heidelberg New York, pp 280-293... 

Biotin is central to the metabolism of carbohydrates, amino acids, and lipids as biotin is the prosthetic group of the carboxylases. In addition to this metabolic function, biotin influences transcription in organisms ranging from bacteria to humans. Biotin exerts complex effects on cell cycle and gene transcription through epigenetic mechanisms. Nuclear biotin holocarboxylase synthetase seems to interact with other chromatin proteins to form a multiprotein gene repressor complex. 

BrdUrd is a well-known mutagen causing base-pairing errors, which result mainly in transition of the adenine-thymine base pair to guanine-cytosine. BrdUrd also induces SCEs, causes chromosome aberrations, increases radiosensitivity, alters binding affinity of chromatin proteins, and has several other effects on cells that may or may not be related to its substitution into DNA. Thus, it is possible that cells containing BrdUrd do not show the same response to chemicals in terms of SCEs, aberrations, or mutations as do untreated cells. 

There have been two basic approaches. First one involves isolation of the chromatin and nucleosome from the healthy and diseased cell line. The second approach is the reconstitution of the model target such as nucleosome followed by the association with the drug(s). The second approach has been extensively employed to identify the binding site in the protein-nucleic acid complex. A pre-knowledge about the components and their arrangements in the reconstituted system sometime makes it the preferred approach. Different biophysical, biochemical and genetic techniques have been employed to understand the mode of association and the effect of the drugs upon chromatin/nucleosome structure and function. 

Figure 1. Mechanistic effect of acetylation/deacetylation of histones and nonhistones on chromatin stracture.(a) Acetylation of non-histone proteins results in transcriptional activation (b) Acetylation of ORCl by HBOl is important for replication, (c) Acetylation of newly synthesized...

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