Among these interactions is the RNA binding protein Ataxin-2 binding protein 1 (A2BP1), [41]. Ataxin-2 and A2BP1 interact and colocalize in vivo, but their functional relationship is unknown. Ataxin-2 also binds to the DEAD/H-box RNA helicase DDX6, and the poly(A) binding protein 1 (PABP-C1), both components of P-bodies and stress granules [ 42 and 43]. PABP-C1 also forms a protein–mRNA complex with Ataxin-2 in polyribosomes. In this complex, PABP-C1 and Ataxin-2 bind to each other and each maintain direct contact with

RNA. Interestingly, polyglutamine expansion does not interfere with Ataxin-2 assembly with polyribosomes, suggesting that polyglutamine expansion Epigenetic inhibitor chemical structure of Ataxin-2 might interfere with translational regulation [ 43]. Recently, it was shown that Ataxin-2-mediated regulation of PERIOD translation is required for maintaining circadian

http://www.selleckchem.com/products/iwr-1-endo.html clock function in pacemaker neurons that set daily rhythms for behavior and synchronize transcriptional rhythms to the circadian clock organism-wide [ 44•• and 45••]. Sassone-Corsi and co-workers discuss this process further in this issue. SCA3 is caused by polyglutamine expansion of the Ataxin-3 gene and is the most common inherited cerebellar ataxia in some populations [46]. The Ataxin-3 protein is a transcription factor and can bind directly to gene promoters in chromatin [47]. It is also a Josephin domain-containing ubiquitin protease that binds to and deubiquitinates poly-ubiquitin chains on histone H2B [48]. Ataxin-3 normally interacts with numerous transcriptional regulators including the forkhead box O (FOXO)-4 transcription factor, TATA-binding protein-associated factor TAFII130 [56], CBP [57], nuclear co-repressor receptor NCoR [49], histone deacetylases [47], and DNA repair protein RAD23 [50]. Thus, it seems capable of recruiting transcriptional regulators to gene promoters through its interactions with both DNA binding proteins and non-DNA binding chromatin regulatory factors. Once there, it can function to deubiquitinate histone H2B. Interestingly, Ataxin-3 ubiquitin protease activity is indispensable

for gene activation [47]. Upon oxidative stress, Ataxin-3 shuttles with the FOXO-4 transcription factor into the Endonuclease nucleus, where they bind and activate the manganese superoxide dismutase (SOD2) gene promoter. Polyglutamine expansion impairs Ataxin-3 transactivation function by preventing recruitment of co-activators, and SOD2 expression is reduced in the brains of SCA3 patients [51••]. It is tempting to speculate that histone deubiquitination is disrupted in SCA3 and that a balance of H2B ubiquitination is important for maintenance of neural stability. Wild-type Ataxin-3 can also recruit histone deacetylase 3 (HDAC3) and nuclear receptor corepressor 1 (NCoR) to the matrix metalloproteinase-2 (MMP-2) promoter, resulting in histone deacetylation and transcriptional repression [47].