It takes a PHD to SUMO

ArticleinTrends in Biochemical Sciences 33(5):191-4 · June 2008with2 Reads
Impact Factor: 11.23 · DOI: 10.1016/j.tibs.2008.02.003 · Source: PubMed
Abstract

PHD fingers and bromodomains are found in close proximity to each other in many chromatin-associated proteins and can functionally synergize. Recently, it has been demonstrated that the PHD finger of the KAP1 co-repressor functions as an E3 SUMO ligase for the adjacent bromodomain. This PHD-mediated SUMOylation stabilizes the association of the bromodomain with the chromatin modifiers SETDB1 and the nucleosome remodeling and deacetylation (NuRD) complex, thereby promoting establishment of the silent gene expression state.

    • "These structural domains are mostly found in nuclear proteins that bind to nucleosomes [33]. It was also demonstrated that PHDs are capable to read the histone modifications [34] and can act as E3 SUMO ligase as well [35], thus corroborating their role in the regulation of transcriptional activity. In addition, SPBP was found to be SUMOylated on its nucleosome binding region [32], while RAI1 has several putative SUMOylation sites (mapping most of them at the N-terminal half). "
    [Show abstract] [Hide abstract] ABSTRACT: Smith-Magenis Syndrome (SMS) is a complex genomic disorder mostly caused by the haploinsufficiency of the Retinoic Acid Induced 1 gene (RAI1), located in the chromosomal region 17p11.2. In a subset of SMS patients, heterozygous mutations in RAI1 are found. Here we investigate the molecular properties of these mutated forms and their relationship with the resulting phenotype. We compared the clinical phenotype of SMS patients carrying a mutation in RAI1 coding region either in the N-terminal or the C-terminal half of the protein and no significant differences were found. In order to study the molecular mechanism related to these two groups of RAI1 mutations first we analyzed those mutations that result in the truncated protein corresponding to the N-terminal half of RAI1 finding that they have cytoplasmic localization (in contrast to full length RAI1) and no ability to activate the transcription through an endogenous target: the BDNF enhancer. Similar results were found in lymphoblastoid cells derived from a SMS patient carrying RAI1 c.3103insC, where both mutant and wild type products of RAI1 were detected. The wild type form of RAI1 was found in the chromatin bound and nuclear matrix subcellular fractions while the mutant product was mainly cytoplasmic. In addition, missense mutations at the C-terminal half of RAI1 presented a correct nuclear localization but no activation of the endogenous target. Our results showed for the first time a correlation between RAI1 mutations and abnormal protein function plus they suggest that a reduction of total RAI1 transcription factor activity is at the heart of the SMS clinical presentation.
    Full-text · Article · Sep 2012 · PLoS ONE
    0Comments 13Citations
    • "This loop may, at least for SPBP, have a regulatory role, since a cluster of phosphorylation sites is identified in more than five published high-throughput mass spectrometric identifications of phosphorylation sites in cellular proteins (http://www.phosphosite.org). The ePHD/ADD domains of DNMT3A/L and ATRX are reported to recognize histone modification marks associated with transcriptional repression [20,21,44]. However, some ePHD/ADD-containing proteins are associated with transcriptional activation, such as the MLL family and trithorax homologues which are associated with establishment of H3K4 methylation (reviewed in [48]). "
    [Show abstract] [Hide abstract] ABSTRACT: Transcriptional regulation requires co-ordinated action of transcription factors, co-activator complexes and general transcription factors to access specific loci in the dense chromatin structure. In the present study we demonstrate that the transcriptional co-regulator SPBP [stromelysin-1 PDGF (platelet-derived growth factor)-responsive element binding protein] contains two independent chromatin-binding domains, the SPBP-(1551-1666) region and the C-terminal extended PHD [ePHD/ADD (extended plant homeodomain/ATRX-DNMT3-DNMT3L)] domain. The region 1551-1666 is a novel core nucleosome-interaction domain located adjacent to the AT-hook motif in the DNA-binding domain. This novel nucleosome-binding region is critically important for proper localization of SPBP in the cell nucleus. The ePHD/ADD domain associates with nucleosomes in a histone tail-dependent manner, and has significant impact on the dynamic interaction between SPBP and chromatin. Furthermore, SPBP and its homologue RAI1 (retinoic-acid-inducible protein 1), are strongly enriched on chromatin in interphase HeLa cells, and both proteins display low nuclear mobility. RAI1 contains a region with homology to the novel nucleosome-binding region SPBP-(1551-1666) and an ePHD/ADD domain with ability to bind nucleosomes. These results indicate that the transcriptional co-regulator SPBP and its homologue RAI1 implicated in Smith-Magenis syndrome and Potocki-Lupski syndrome both belong to the expanding family of chromatin-binding proteins containing several domains involved in specific chromatin interactions.
    Full-text · Article · Nov 2011 · Biochemical Journal
    0Comments 11Citations
    • "It has alternatively been proposed that HDAC4 enhances SUMOylation by other means, such as promoting the phosphorylation of target proteins at sites adjacent to conjugated lysine residues (Yang and Gregoire, 2006). The human co-repressor KRAB-associated protein 1 (KAP1) possesses PHD-finger domains that catalyze intramolecular SUMOylation of an adjacent KAP1 bromodomain (Peng and Wysocka, 2008). SUMOylation stabilizes the association of the bromodomain with the chromatin modifiers, thus promoting the establishment of gene silencing. "
    Full-text · Article · Dec 2009 · Journal of Cell Science
    0Comments 75Citations
Show more

Similar publications