Disease relevance of CXXC1

• MBD1, MBD2 and CGBP genes at chromosome 18q21 are infrequently mutated in human colon and lung cancers [1].
• LCX, leukemia-associated protein with a CXXC domain, is fused to MLL in acute myeloid leukemia with trilineage dysplasia having t(10;11)(q22;q23) [2].
• E7 is structurally and functionally related to Adenovirus E1A protein, which also has two CXXC motifs in CR3 [3].
• We have examined the role of the active-site CXXC central dipeptides of DsbA and DsbC in disulfide bond formation and isomerization in the Escherichia coli periplasm [4].
• Functional analysis of the CXXC motif using phage antibodies that cross-react with protein disulphide-isomerase family proteins [5].

High impact information on CXXC1

• Thioredoxin (Trx) is a ubiquitous intracellular protein disulfide oxidoreductase with a CXXC active site that can be released by various cell types upon activation [6].
• We find that Mbd1a, a major mouse isoform, contains a CXXC domain (CXXC-3) that binds specifically to nonmethylated CpG, suggesting an explanation for methylation-independent localization [7].
• Point mutations in the CXXC domain that eliminate myeloid transformation by an MLL fusion protein also abolished recognition and binding of nonmethylated CpG DNA sites in vitro and transactivation in vivo [8].
• CpG binding protein is crucial for early embryonic development [9].
• In vitro blastocyst outgrowth assays revealed that CGBP-null blastocysts are viable and capable of hatching and forming both an inner cell mass and a trophectoderm [9].

Chemical compound and disease context of CXXC1

• By using the isolated phage antibodies, we demonstrated for the first time that a lysine residue following the CXXC motif significantly increases the isomerase activities of PDI family proteins [5].

Biological context of CXXC1

• Furthermore, the introduction of a CpG dinucleotide into an unrelated oligonucleotide sequence is sufficient to produce a binding site for hCGBP [10].
• These data indicate that hCGBP is a transcriptional activator that recognizes unmethylated CpG dinucleotides, suggesting a role in modulating the expression of genes located within CpG islands [10].
• Ligand screening was utilized to isolate a human cDNA that encodes a novel CpG binding protein, human CpG binding protein (hCGBP) [10].
• CGBP exhibits a punctate nuclear localization correlated with 4,6-diamidino-2-phenylindole light regions and is excluded from metaphase chromosomes [11].
• CGBP associates with the nuclear matrix, and fragments of CGBP that fail to associate with the nuclear matrix fail to localize to nuclear speckles and exhibit reduced transcriptional activation activity [11].

Anatomical context of CXXC1

• CpG-binding protein is a nuclear matrix- and euchromatin-associated protein localized to nuclear speckles containing human trithorax. Identification of nuclear matrix targeting signals [11].
• For CXXC sequence containing MBD1, both protein and mRNA were expressed in cancer cell lines, cancer tissues, BPH-1 cell line, and BPH tissues [12].
• We examined the expression of PCCX1 during cellular aging and immortalization of SV40-transformed human fibroblasts [13].
• A single murine CGBP transcript of approximately 2.6 kb was detected in a wide variety of adult tissues as well as embryonic stem cells [14].

Associations of CXXC1 with chemical compounds

• Specific mutation to alanine of individual conserved cysteine residues within the CXXC domain abolishes DNA binding activity [15].
• Together with the previous finding of reduced levels of cytosine methylation, these data indicate that cells lacking CFP1 contain reduced levels of heterochromatin [16].
• Mutation of the CpG motif(s) present within ligand-selected oligonucleotides ablates the interaction with CpG-binding protein, and mutation to thymine of the nucleotides flanking the CpG motifs reduces the affinity of CpG-binding protein [15].
• CpG-binding protein contains a cysteine-rich CXXC domain that is conserved in DNA methyltransferase 1, methyl binding domain protein 1, and human trithorax [15].
• CpG-binding protein (CXXC finger protein 1 (CFP1)) binds to DNA containing unmethylated CpG motifs and is required for mammalian embryogenesis, normal cytosine methylation, and cellular differentiation [16].

Other interactions of CXXC1

• In the present study, we have investigated the significance of MBD, CXXC, and the C-terminal transcriptional repression domain (TRD) in MBD1 [17].
• A third cysteine-rich domain conforms to the CXXC motif identified in DNA methyltransferase, human trithorax, and methyl-CpG binding domain protein 1 [10].
• We identified a novel gene PCCX1 that encoded a nuclear protein carrying a PHD finger, a CXXC domain, and an acidic region [13].

Analytical, diagnostic and therapeutic context of CXXC1

• The DNA-binding activity of native hCGBP is apparent in electrophoretic mobility shift assays, and hCGBP trans-activates promoters that contain CpG motifs but not promoters in which the CpG is ablated [10].
• Confocal microscopy reveals that CFP1 and Set1 co-localize to nuclear speckles associated with euchromatin [16].
• X-ray crystallography revealed that the CXXC motif, through its network of hydrogen bonds, plays a crucial role in orienting the substrate optimally for catalysis [18].
• Molecular cloning of a zinc finger autoantigen transiently associated with interphase nucleolus and mitotic centromeres and midbodies. Orthologous proteins with nine CXXC motifs highly conserved from nematodes to humans [19].
• To explore further the mechanistic details of this CXXC center, mutants of the Cys residues at positions 315 and 318 of hBCATm were individually and in combination converted to alanine or serine by site-directed mutagenesis (C315A, C315S, C318A, C318S, C315/318A, and C315/318S) [20].

References