scholarly journals Arsenite Binds to the RING Finger Domain of FANCL E3 Ubiquitin Ligase and Inhibits DNA Interstrand Crosslink Repair

2017 ◽  
Vol 12 (7) ◽  
pp. 1858-1866 ◽  
Author(s):  
Ji Jiang ◽  
Marina Bellani ◽  
Lin Li ◽  
Pengcheng Wang ◽  
Michael M. Seidman ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
Ring Finger Domain ◽  
Interstrand Crosslink ◽  
Interstrand Crosslink Repair ◽  
Crosslink Repair

Frequent Detection of C-Cbl Homozygous Mutation in Secondary Myelogeneous Leukemia Transformed from MDS/MPD with Chromosome 11q Uniparental Disomy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 851-851 ◽  
Author(s):  
Hideki Makishima ◽  
Andrew J Dunbar ◽  
Anna M Jankowska ◽  
Lukasz P. Gondek ◽  
Eric D Hsi ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Copy Number ◽  
Poor Prognosis ◽  
Uniparental Disomy ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
Blast Transformation ◽  
Missense Mutations ◽  
Ring Finger Domain ◽  
History Of

Abstract Two types of acquired loss of heterozygosity are possible in cancer: deletions and copy-neutral uniparental disomy (UPD). Conventionally, copy number losses are identified using metaphase cytogenetics while detection of UPD is accomplished by microsatellite and copy number analysis and as such, is not often used clinically. Recently, introduction of single nucleotide polymorphism microarrays (SNP-A) have allowed for the systematic and sensitive detection of UPD in hematological malignancies and other cancers. In this study, we have applied Affymetrics 250K and 6.0 SNP-A technology to detect previously cryptic chromosomal changes, particularly UPD, in a cohort of 301 patients with myelodysplastic syndromes (MDS), overlap MDS/myeloproliferative disorders (MPD), MPD, and primary and secondary acute myeloid leukemia (AML). When appropriate, germ line DNA was analyzed to confirm somatic nature of the suspected lesions. We show that UPD is a common chromosomal defect in myeloid malignancies, particularly in chronic myelomonocytic leukemia (CMML; 52%) and MDS/MPD-unclassifiable (49%). Furthermore, we demonstrate that mapping minimally overlapping segmental UPD regions can help target the search for both known and unknown pathogenic mutations. Chromosomes frequently affected by UPD include 1p (N=12), 4q (N=11), 6p (N=9), 7q (N=9), 9p (N=11), 13 (N=11), 17 (N=11), and 21 (N=7). The chromosome arm most often affected was 11q, occurring in 15/301 patients, 8 of which had MDS/MPDu, CMML or AML evolving from these conditions. These patients with UPD11q appear to display several common clinical phenotypic trends, including history of MDS/MPD, the presence of monocytic blasts or increased numbers of differentiated monocytes, propensity to transformation, and poor prognosis. Given the prevalence of UPD on chromosome 11q, we screened for candidate genes located in this region. Among our UPD11q cohort, the lesions of 12/15 patients were located in the region of the c-Cbl gene encoding the E3 ubiquitin ligase involved in the degradation of active protein tyrosine kinase receptors. Direct genomic sequencing of c-Cbl in these patients revealed the presence of 3 unique missense mutations, all occurring within or directly adjacent to the RING finger domain responsible for ubiquitination activity. In total, 7/12 patients with UPD11q showed c-Cbl mutation. One mutation, occurring in 2/7 patients, resulted in the substitution of an arginine with either glutamine or proline at position 420 (R420Q/P) located just outside the RING domain. However, we also found 2 additional, newly-identified missense mutations, both affecting the cysteines of the RING finger in the remaining 5 patients. In 2/5 patients, residue 384 was altered by substitution of a tyrosine. In the other 3 patients, residue 404 was altered by substitution of either a tyrosine (in 1 patient) or serine (in 2 patients). When additional 71 patients with similar phenotypic features but negative for UPD11q were screened, 2 novel c-Cbl mutations in RING finger domain (heterozygous) and Linker sequence (monoallelic in deletion 11q) were identified to a total of 9 cases affected by c-Cbl mutations. Analysis of clinical/immunological/pathological phenotype of these patients revealed the history of blast transformation in 77%, presence of monocytosis (over 1000/ul) or monocytic blasts in 88%, poor prognosis in 100% (5 years over all survival; 0%), some degree of marrow fibrosis in 100% and c-kit positivity in 77% of cases. We conclude that invariant mutations in c-Cbl E3 ubiquitin ligase may explain the pathogenesis of a clonal process or subsequent AML transformation in a unique subset of MDS/MPD, including CMML.

scholarly journals Zinc Binding Properties of Engineered RING Finger Domain of Arkadia E3 Ubiquitin Ligase

2010 ◽  
Vol 2010 ◽  
pp. 1-7 ◽  
Author(s):  
Christos T. Chasapis ◽  
Ariadni K. Loutsidou ◽  
Malvina G. Orkoula ◽  
Georgios A. Spyroulias
Keyword(s):  
Ubiquitin Ligase ◽  
Structural Integrity ◽  
Recombinant Expression ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
Ring Domain ◽  
Site Directed Mutagenesis ◽  
Zinc Binding ◽  
Ring Finger Domain ◽  
C Terminus

Human Arkadia is a nuclear protein consisted of 989 amino acid residues, with a characteristic RING domain in its C-terminus. The RING domain harbours the E3 ubiquitin ligase activity needed by Arkadia to ubiquitinate its substrates such as negative regulators of TGF- signaling. The RING finger domain of Arkadia is a RING-H2 type and its structure and stability is strongly dependent on the presence of two bound Zn(II) ions attached to the protein frame through a defined Cys3-His2-Cys3 motif. In the present paper we transform the RING-H2 type of Arkadia finger domain to nonnative RING sequence, substituting the zinc-binding residues or to Arginine, through site-directed mutagenesis. The recombinant expression, inEscherichia coli, of the mutants C955R and H960R reveal significant lower yield in respect with the native polypeptide of Arkadia RING-H2 finger domain. In particular, only the C955R mutant exhibits expression yield sufficient for recombinant protein isolation and preliminary studies. Atomic absorption measurements and preliminary NMR data analysis reveal that the C955R point mutation in the RING Finger domain of Arkadia diminishes dramatically the zinc binding affinity, leading to the breakdown of the global structural integrity of the RING construct.

scholarly journals The RING Finger Domain of Varicella-Zoster Virus ORF61p Has E3 Ubiquitin Ligase Activity That Is Essential for Efficient Autoubiquitination and Dispersion of Sp100-Containing Nuclear Bodies

2010 ◽  
Vol 84 (13) ◽  
pp. 6861-6865 ◽  
Author(s):  
Matthew S. Walters ◽  
Christos A. Kyratsous ◽  
Saul J. Silverstein
Keyword(s):  
Varicella Zoster Virus ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
Nuclear Bodies ◽  
Ring Finger Domain ◽  
Varicella Zoster ◽  
Ubiquitin Ligase Activity ◽  
Protein Icp0 ◽  
Simplex Virus

ABSTRACT Varicella zoster virus encodes an immediate-early (IE) protein termed ORF61p that is orthologous to the herpes simplex virus IE protein ICP0. Although these proteins share several functional properties, ORF61p does not fully substitute for ICP0. The greatest region of similarity between these proteins is a RING finger domain. We demonstrate that disruption of the ORF61p RING finger domain by amino acid substitution (Cys19Gly) alters ORF61p intranuclear distribution and abolishes ORF61p-mediated dispersion of Sp100-containing nuclear bodies. In addition, we demonstrate that an intact ORF61p RING finger domain is necessary for E3 ubiquitin ligase activity and is required for autoubiquitination and regulation of protein stability.

scholarly journals HerpesSimplex Virus 1 Mutant in Which the ICP0 HUL-1 E3 Ubiquitin Ligase SiteIs Disrupted Stabilizes cdc34 but Degrades D-Type Cyclins andExhibits DiminishedNeurotoxicity

2003 ◽  
Vol 77 (24) ◽  
pp. 13194-13202 ◽  
Author(s):  
Ryan Hagglund ◽  
Bernard Roizman
Keyword(s):  
Amino Acids ◽  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
Cell Protein ◽  
Ring Finger Domain ◽  
Exon 2 ◽  
Multifunctional Protein ◽  
Infected Cells

ABSTRACT Herpes simplex virus type 1 (HSV-1) infected cell protein 0 (ICP0) is a multifunctional protein that functions as a promiscuous transactivator and promotes the degradation of multiple cellular proteins. In vitro studies indicated that it encodes two physically separated functional E3 ubiquitin ligase domains. One, designated herpesvirus ubiquitin ligase 1 (HUL-1), maps to a region encoded by exon 3 and is contained between residues 543 and 680. Deletion of amino acids 621 to 625 abolishes this activity. The second, designated HUL-2, maps to the RING finger domain present in ICP0 encoded by exon 2. Earlier studies have shown that ICP0 stabilizes cyclins D1 and D3, and several lines of investigation led to the hypothesis that this function of ICP0 is the consequence of degradation of the E2 enzyme cdc34, known to be involved in the proteasome-dependent degradation of D-type cyclins. Consistent with this hypothesis, we have previously shown that cdc34 physically interacts with ICP0 at or near aspartate 199 and at amino acids 621 to 625 and that the former site is required for effective ubiquitylation and degradation of cdc34. Furthermore, the ICP0 HUL-1 domain promotes the polyubiquitination of cdc34 in vitro. If the mechanism by which D-type cyclins are salvaged in wild-type-infected cells is dependent on polyubiquitination and consequent destruction of cdc34, than the mutant virus R6701, which was constructed for these studies and lacks ICP0 residues 621 to 625, should destabilize the D cyclins and preclude the degradation of cdc34. We report that ICP0 residues 621 to 625 are essential for degradation of cdc34 in infected cells and for the ICP0-mediated stabilization of D-type cyclins, that a mutation that specifically disrupted the ring finger domain of the HUL-2 site had no effect on the degradation of cdc34 in infected cells, and that deletion of ICP0 residues 621 to 625 decreased the replicative capacity of the virus in growth-arrested but not in dividing cells and resulted in diminished pathogenicity on intracerebral inoculation of mice. We conclude that the ICP0 HUL-1 domain acts in infected cells to degrade cdc34 and that this function requires the interaction of cdc34 with sequences in exons 2 and 3 but does not involve the HUL-2 RING finger E3 domain.

scholarly journals Structural and functional characterization of hMEX-3C Ring finger domain as an E3 ubiquitin ligase

2018 ◽  
Vol 27 (9) ◽  
pp. 1661-1669 ◽  
Author(s):  
Sayed Ala Moududee ◽  
Yiyang Jiang ◽  
Nshogoza Gilbert ◽  
Guodong Xie ◽  
Zheng Xu ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Functional Characterization ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
Ring Finger Domain

scholarly journals RBBP6, a RING finger-domain E3 ubiquitin ligase, induces epithelial–mesenchymal transition and promotes metastasis of colorectal cancer

2019 ◽  
Vol 10 (11) ◽  
Author(s):  
Chao Xiao ◽  
Gang Wu ◽  
Zhijie Zhou ◽  
Xin Zhang ◽  
YuPeng Wang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Ubiquitin Ligase ◽  
Nuclear Translocation ◽  
Epithelial Mesenchymal Transition ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
Migration And Invasion ◽  
Ring Finger Domain ◽  
Mesenchymal Transition ◽  
Cell Metastasis

Abstract RBBP6 has been implicated in tumorigenesis but its role in tumor metastasis and progression has not been evaluated. Interestingly, here we show that RBBP6 is upregulated in colorectal cancer (CRC) where its expression level is positively correlated with distant metastasis. In this study, we identified RBBP6, a RING Finger-domain E3 ubiquitin ligase, served as an independent prognostic factor and predicted poor outcome for CRC patients. RBBP6 promoted cell proliferation, migration, and invasion in CRC cells and promoted tumor growth, lung metastasis, and liver metastasis in mouse models. Mechanistically, we revealed that RBBP6 bound and ubiquitylated IκBα, an inhibitor of the NF-κB-signaling pathway. RBBP6-mediated ubiquitination and degradation of IκBα significantly enhanced p65 nuclear translocation, which triggered the activation of NF-κB pathway and then induced the epithelial–mesenchymal transition (EMT) process and cell metastasis. Furthermore, by DNA methylation results and ChIP analysis, we demonstrated that the promoter of RBBP6 was hypomethylated, and was activated by multi-oncogenic transcription factors. In conclusion, our findings suggest that RBBP6 may be a potential prognostic biomarker and therapeutic target for CRC invasion and metastasis.

The PA-TM-RING protein RING finger protein 13 is an endosomal integral membrane E3 ubiquitin ligase whose RING finger domain is released to the cytoplasm by proteolysis

FEBS Journal ◽  
2009 ◽  
Vol 276 (7) ◽  
pp. 1860-1877 ◽  
Author(s):  
Jeffrey P. Bocock ◽  
Stephanie Carmicle ◽  
Saba Chhotani ◽  
Michael R. Ruffolo ◽  
Haitao Chu ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
E3 Ubiquitin Ligase ◽  
Ring Finger ◽  
Ring Finger Protein ◽  
Ring Finger Domain ◽  
Finger Protein
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