Additional sex combs-like protein 1 (ASXL1) is the vertebrate homologue of Drosophila additional sex combs []. ASXL1 is a polycomb group (PcG) protein. PcG proteins act by forming multiprotein complexes, which are required to maintain the transcriptionally repressive state of homeotic genes throughout development. ASX is a non-catalytic component of the polycomb repressive deubiquitinase (PR-DUB) complex, consisting at least of BAP1 and ASX. The PR-DUB complex specifically mediates the removal of monoubiquitin from H2A [].
Protein ubiquitination is a fundamental mechanism that affects nearly all aspects of cellular life. Deubiquitinating enzymes (DUBs) play important roles in ubiquitin (Ub) signalling by Ub cleavage from adducts. The Ub C-terminal hydrolase (UCH) family of deubiquitinases (DUBs) contains four members including UCH37 (also called ubiquitin carboxy-terminal hydrolase isozyme L5, UCHL-5) and BAP1 which share high similarity in the catalytic domain (UCH) and the C-terminal region, termed the UCH37-like domain (ULD) which is responsible for binding interaction partners and is also involved in the regulation of DUB activity. ULD from BAP1 and UCH-L5 binds the DEUBiquitinase ADaptor (DEUBAD) domain present in their interacting partners, e.g., ASXL1 for BAP1, and RPN13 (ADRM1) and INO80G (NFRKB) for UCH-L5 [, , , , ].This entry represents the DEUBAD domain which consists of eight α-helices that form a helical bundle surrounding a compact hydrophobic core []. It has a modular architecture with the core formed by helices 1-4, primarily responsible for binding to ULD, and accessory elements that lead to full activation, or inhibition, of the UCH activity [, ].
This domain, known as the HARE-HTH domain, adopts the winged helix-turn-helix fold and is predicted to bind DNA. It can be found at the N terminus of the ASXL protein. It can also be found in several other eukaryotic chromatin proteins (such as HB1 in plants), diverse restriction endonucleases and DNA glycosylases, the RNA polymerase delta subunit of Gram-positive bacteria and certain bacterial proteins that combine features of the RNA polymerase alpha-subunit and sigma factors []. The genetic interaction of the HARE-HTH containing ASXL with the methyl cytosine hydroxylating Tet2 protein is suggestive of a role for the domain in discriminating sequences with DNA modifications such as hmC []. Bacterial versions include fusions to diverse restriction endonucleases, and a DNA glycosylase where it may play a similar role in detecting modified DNA. Certain bacterial version of the HARE-HTH domain show fusions to the helix-hairpin-helix domain of the RNA polymerase alpha subunit and the HTH domains found in regions 3 and 4 of the sigma factors []. These versions are predicted to function as a novel inhibitor of the binding of RNA polymerase to transcription start sites, similar to the Bacillus delta protein [, ].This domain consists of four α-helices (helices I-II-III-IV) and an antiparallel β-sheet composed of three short β-strands at the top of a "twisted tripod"formed by helices II, III, and IV [].The Asx-like (Asxl) proteins includes Asxl1-3. They are putative Polycomb group (PcG) proteins, which act by forming multiprotein complexes that are required to maintain the transcriptionally repressive state of homeotic genes throughout development. Asxl1 is involved in transcriptional regulation mediated by ligand-bound retinoic acid receptors (RARs) and peroxisome proliferator-activated receptor gamma (PPARG) [].The delta protein is a dispensable subunit of Bacillus subtilis RNA polymerase (RNAP) that has major effects on the biochemical properties of the purified enzyme. In the presence of delta, RNAP displays an increased specificity of transcription, a decreased affinity for nucleic acids, and an increasedefficiency of RNA synthesis because of enhanced recycling []. The delta protein, contains two distinct regions, an N-terminal domain and a glutamate and aspartate residue-rich C-terminal region []. It participates in both the initiation and recycling phases of transcription.
