Ellipticine australia br Conclusions and future directions I
Conclusions and future directions In recent years we saw major advances in our knowledge of H2A-DUB biology, with discovery of novel mammalian H2A-DUBs, better understanding of their biochemical properties, and development of several animal models to address their in vivo functions. However at present it remains difficult to determine how these diverse chromatin-interacting enzymes cooperate in situ to establish and regulate the genomic landscape of histone H2A (de)ubiquitination. Although many H2A-DUBs have been linked to transcriptional regulation of specific target genes, global picture of transcriptional regulation by H2A-DUBs is current missing. Unbiased mapping of H2A-DUB protein localization across mammalian genome in select cell types, such as ES-cells and others, would be highly valuable. Combined with similar existing datasets for polycomb proteins, core ES-cells transcriptional regulators, and histone modifications, it would yield a detailed picture of H2A-DUB functions within transcriptional networks. Further work is then needed to address H2A-DUB interactions with various Ellipticine australia remodeling protein complexes and transcription factors, in order to establish the mechanisms through which they are recruited to their specific genomic locations. Finally, the relationship between the catalytic activity of H2A-DUBs and their cellular functions need to be addressed. As most H2A-DUBs are multifunctional proteins and parts of interactive multi-subunit complexes, knockout studies alone are often insufficient to attribute specific functions to catalytic activity. Utilization of functional mutants that lack specific catalytic and binding activities will help to address this, while systematic knockout of multiple DUBs could further define redundancies in their functions. With these and other studies, the H2A-DUB class of chromatin modifying proteins will emerge as an important epigenetic regulator of cellular chromatin states, working in concert with H2AUb ‘writers’ and ‘readers’ to regulate the transcriptional landscapes and genomic stability of mammalian cells.
Acknowledgements This work was funded by the Canadian Institutes for Health Research (CIHR), the Canadian Foundation for Innovation (CFI), and Startup Funds from the McGill University Faculty of Medicine. AN is a Tier 2 Canada Research Chair in Hematopoiesis and Lymphocyte Differentiation.
The regulation of intracellular protein turnover is essential for all eukaryotic cells. In general, this process is mediated by either lysosomal degradation or ubiquitin-mediated proteasomal degradation . Protein degradation by the ubiquitin–proteasome pathway is required for a variety of cellular processes including signal transduction, cell cycle regulation, apoptosis, transcriptional activation, antigen presentation, and DNA repair . A number of ubiquitinating and deubiquitinating enzymes involved in proteasome-mediated protein degradation have been isolated , . These enzymes are complementary, and mediate the status for the conjugation of ubiquitin. Proteins are initially conjugated to the ubiquitin (Ub), a small polypeptide of 76 amino acids, which serves as a signal , . Several classes of enzymes including ubiquitin-activating enzymes (E1), ubiquitin carrier proteins (E2), and ubiquitin ligases (E3) are required for the conjugation of Ub to protein targets , , . Conjugated proteins with ubiquitins are next recognized and degraded by the proteasome, a multisubunit protein degradation complex . Deubiquitinating enzymes, classified as ubiquitin carboxyl-terminal hydrolases (UCHs), ubiquitin-specific processing proteases (UBPs), Jab1/Pad1/MPN-domain metallo-enzyme (JAMMs), ubiquitin-like proteases (ULPs), and ovarian tumor (OTU)-domain Ub-aldehyde-binding protein (OTUs), function to remove ubiquitin and a large number of superfamily has been identified , , . Interestingly, these polypeptides have various lengths and are complex in their structures . While there is little amino acid sequence homology throughout their coding regions, sequence comparison revealed three conserved domains that may be essential for the catalytic site of the enzymes , , .