It takes a PHD to SUMO

Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Trends in Biochemical Sciences (Impact Factor: 11.23). 06/2008; 33(5):191-4. DOI: 10.1016/j.tibs.2008.02.003
Source: PubMed


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.

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    • "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). "
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    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.
    PLoS ONE 09/2012; 7(9):e45155. DOI:10.1371/journal.pone.0045155 · 3.23 Impact Factor
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    • "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. "

    Journal of Cell Science 12/2009; 122(Pt 23):4249-52. DOI:10.1242/jcs.050542 · 5.43 Impact Factor
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    ABSTRACT: Mutations can be beneficial under conditions in which genetic diversity is advantageous, such as somatic hypermutation and antibody generation, but they can also be lethal when they disrupt basic cellular processes or cause uncontrolled proliferation and cancer. Mutations arise from inaccurate processing of lesions generated by endogenous and exogenous DNA damaging agents, and the genome is particularly vulnerable to such damage during S phase. In this phase of the cell cycle, many lesions in the DNA template block replication. Such lesions must be bypassed in order to preserve fork stability and to ensure completion of DNA replication. Lesion bypass is carried out by a set of error-prone and error-free processes collectively referred to as DNA damage tolerance mechanisms. Here, we discuss how two types of DNA damage tolerance, translesion synthesis and template switching, are regulated at stalled replication forks by ubiquitination of PCNA, and the conditions under which they occur.
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