Raltegravir is an antiretroviral drug produced by Merck and Co

by Selleckchem | Dec 12 2012

Epigenetic marks play a major role in the control of cell fate during mammalian development. Among these, the most studied so far is lysine acetylation, a posttranslational modification of histones which inactivates the positive Raltegravir charge of lysines. Histone hyperacetylation largely correlates with transcription . In agreement with this correlation, histone acetyltransferases HATs are mostly involved in transcriptional activation, whereas histone deacetylases HDACs are often corepressors. The effect of Lenalidomide histone acetylation on chromatin function could be mediated by direct effects on nucleosome structure or nucleosome nucleosome interactions. However, acetylated lysines are also specifically recognized by the socalled bromodomain, a protein domain present in many chromatin related proteins . The recruitment of activating proteins containing bromodomains to acetylated histones can bring about transcriptional activation . HDAC belongs to the class I histone deacetylase in mammals, which means that its yeast homolog is RPD.
It belongs to a multimolecular complex whose subunits, such as the NCoR protein, are required for HDAC enzymatic activity HDAC functions as a Raf Inhibitors corepressor for many sequence specific transcription factors, including NF B, EF Rb, and c jun Through a physical interaction with these transcription factors, HDAC is recruited to specific promoters, where it brings about transcriptional repression through histone deacetylation. In addition to this local function, HDAC is also important for global genome wide histone deacetylation and specific inactivation of HDAC leads to an increase in global histone acetylation Finally, HDAC can also deacetylate nonhistone proteins and it is unclear at this moment whether its role in transcription is mediated though the deacetylation of histones or other transcription factors. Little is known about HDAC regulation. Recently, it was shown that its activity is regulated by protein phosphatase . Moreover, HDAC possesses a unique property among class I HDACs, localizing in both the cytoplasm and the nucleus . Indeed, it contains a nuclear localization signal NLS at its C terminus and two Lapatinib different nuclear export sequences have been proposed Moreover, its subcellular localization is known to be regulated through a physical interaction with Tab, which induces HDAC relocalization to the cytoplasm following interleukin treatment .
Importantly, HDAC seems to be critical for the control of apoptosis. Many transcription factors regulated by HDAC are important for apoptosis, including NF B and EF Moreover, the inactivation of HDAC in chicken or mammalian cells leads to apoptosis induction , or favors apoptosis . Specific modifications of chromatin are likely to play an important role in apoptosis control. Indeed, the induction of histone hyperacetylation using HDAC inhibitors is often sufficient to induce apoptosis . Apoptosis is characterized by major changes in chromatin structure since chromatin is highly compacted and DNA is extensively cleaved. Recent data have shown that apoptosis is accompanied by global changes in histone modifications, such as phosphorylation or ubiquitination Moreover, the activation of GSK-3 Inhibitors proapoptotic genes and the inactivation of antiapoptotic genes, which occur during apoptosis, are accompanied by specific changes in histone modifications at these promoters. Correspondingly to this wave of changes in histone modifications, the activity of many proteins modifying histones is affected during apoptosis, mostly through caspase mediated cleavage . Concerning enzymes controlling histone acetylation levels, it has been observed that the HAT CBP p is cleaved during apoptosis in the central nervous system, leading to the loss of its HAT activity . Recently, another histone deacetylase, HDAC , has also been shown to be a substrate of caspases . Because of the role of HDAC in apoptosis control, we investigated its regulation during apoptosis. We found that HDAC is cleaved during apoptosis, and we demonstrate that this cleavage may participate in the establishment of the apoptotic genetic program.