Kaiso-Deficient Mice Show Resistance to Intestinal Cancer

Prokhortchouk, Anna; Sansom, Owen J.; Selfridge, Jim; Caballero, Isabel Martín; Саложин, С. В.; Aithozhina, D. S.; Cerchietti, Leandro; Meng, Fan; Augenlicht, Leonard H.; Mariadason, John M.; Hendrich, Brian; Melnick, Ari; Prokhortchouk, Egor; Clarke, Alan R.; Bird, Adrian

doi:10.1128/mcb.26.1.199-208.2006

Cited by 145 publications

(162 citation statements)

References 49 publications

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“…4; Table 2) the specific binding of ZBTB33 to the methylated CpG island of the MTA2 gene in vitro (Yoon et al 2003). Strikingly, the absence of ZBTB33 does not detectably alter the expression of MTA2 and other putative ZBTB33 target genes suggesting a redundant function (Prokhortchouk et al 2006). UHRF1, being part of a multiprotein complex containing PCNA and DNMT1 (Supplemental Fig.…”

Section: Determination Of Dna Modification-dependent Protein Interactmentioning

confidence: 99%

A SILAC-based DNA protein interaction screen that identifies candidate binding proteins to functional DNA elements

2008

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Determining the underlying logic that governs the networks of gene expression in higher eukaryotes is an important task in the post-genome era. Sequence-specific transcription factors (TFs) that can read the genetic regulatory information and proteins that interpret the information provided by CpG methylation are crucial components of the system that controls the transcription of protein-coding genes by RNA polymerase II. We have previously described Stable Isotope Labeling by Amino acids in Cell culture (SILAC) for the quantitative comparison of proteomes and the determination of proteinprotein interactions. Here, we report a generic and scalable strategy to uncover such DNA protein interactions by SILAC that uses a fast and simple one-step affinity capture of TFs from crude nuclear extracts. Employing mutated or nonmethylated control oligonucleotides, specific TFs binding to their wild-type or methyl-CpG bait are distinguished from the vast excess of copurifying background proteins by their peptide isotope ratios that are determined by mass spectrometry. Our proof of principle screen identifies several proteins that have not been previously reported to be present on the fully methylated CpG island upstream of the human metastasis associated 1 family, member 2 gene promoter. The approach is robust, sensitive, and specific and offers the potential for high-throughput determination of TF binding profiles.

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Section: Determination Of Dna Modification-dependent Protein Interactmentioning

confidence: 99%

A SILAC-based DNA protein interaction screen that identifies candidate binding proteins to functional DNA elements

2008

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“…The affinity for this sequence is higher that the affinity for methylated CpGs and it could be involved in specific DNA sequences binding (Daniel et al, 2002). Kaiso knockout mice intercrossed with Apc (Min/ þ ) background are less susceptible to intestinal tumours (Prokhortchouk et al, 2002) …”

Section: Other Methylated Cpg-binding Proteinsmentioning

confidence: 99%

Proteins that bind methylated DNA and human cancer: reading the wrong words

2008

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DNA methylation and the machinery involved in epigenetic regulation are key elements in the maintenance of cellular homeostasis. Epigenetic mechanisms are involved in embryonic development and the establishment of tissue-specific expression, X-chromosome inactivation and imprinting patterns, and maintenance of chromosome stability. The balance between all the enzymes and factors involved in DNA methylation and its interpretation by different groups of nuclear factors is crucial for normal cell behaviour. In cancer and other diseases, misregulation of epigenetic marks is a common feature, also including DNA methylation and histone posttranslational modifications. In this scenario, it is worth mentioning a family of proteins characterized by the presence of a methyl-CpGbinding domain (MBDs) that are involved in interpreting the information encoded by DNA methylation and the recruitment of the enzymes responsible for establishing a silenced state of the chromatin. The generation of novel aberrantly hypermethylated regions during cancer development and progression makes MBD proteins interesting targets for their biological and clinical implications. British Journal of Cancer (2008) DNA METHYLATION AND ITS MEDIATORSDNA methylation is one of the most important mechanisms for epigenetic silencing in mammals. It is a key element in heterochromatin formation and maintenance, and is involved in processes such as X-chromosome inactivation and gene imprinting. DNA methylation also occurs at repetitive sequences to ensure chromosome stability. DNA methylation is developed by a family of DNA methyltransferase enzymes (DNMTs) that add a methyl group to the fifth carbon position of cytosine when followed by a guanine nucleotide. Methylation of DNA is accompanied by histone post-translational modifications that modulate DNA function, regulating chromatin structure and determining the transcriptional state of the DNA wrapped around it.The crosstalk between DNA methylation and histone modifications is established by different nuclear factors. Among them, it is particularly remarkable a family of proteins that contain a MethylCpG-binding domain commonly known as MBD proteins that recognises single methylated CpG dinucleotide (Hendrich and Bird, 1998). MBD family members recruit histone modifying and chromatin remodeling complexes to methylated sites. The MBD family of proteins is composed by five members namely MeCP2, MBD1, MBD2, MBD3 and MBD4. MeCP2 was the first characterised member and its 70 amino acids region corresponding to the MBD was used for database identification of the remaining MBD containing proteins. The binding affinity of MBD proteins differs between them, as was demonstrated that MBD2 is the MBD protein with higher methylated DNA-binding affinity in vitro .

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“…The interaction of Kaiso with p120 ctn has been implicated in regulation of canonical and noncanonical Wnt signaling pathways through a mechanism that involves KBS recognition (15, 16). Additionally, there is increasing evidence that Kaiso expression levels are elevated in tumorigenesis, indicating that Kaiso may play a direct role in modulating cancer through transcriptional control of aberrantly methylated and KBS-containing genes (14,19,20). It still is unclear whether the transcriptional regulation of the two distinctly different DNA sequences is synergistic in nature or mutually exclusive.…”

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Molecular basis for recognition of methylated and specific DNA sequences by the zinc finger protein Kaiso

Buck‐Koehntop

Stanfield

Ekiert

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Methylation of CpG dinucleotides in DNA is a common epigenetic modification in eukaryotes that plays a central role in maintenance of genome stability, gene silencing, genomic imprinting, development, and disease. Kaiso, a bifunctional Cys 2 His 2 zinc finger protein implicated in tumor-cell proliferation, binds to both methylated CpG (mCpG) sites and a specific nonmethylated DNA motif (TCCTGCNA) and represses transcription by recruiting chromatin remodeling corepression machinery to target genes. Here we report structures of the Kaiso zinc finger DNA-binding domain in complex with its nonmethylated, sequence-specific DNA target (KBS) and with a symmetrically methylated DNA sequence derived from the promoter region of E-cadherin. Recognition of specific bases in the major groove of the core KBS and mCpG sites is accomplished through both classical and methyl CH···O hydrogen-bonding interactions with residues in the first two zinc fingers, whereas residues in the C-terminal extension following the third zinc finger bind in the opposing minor groove and are required for high-affinity binding. The C-terminal region is disordered in the free protein and adopts an ordered structure upon binding to DNA. The structures of these Kaiso complexes provide insights into the mechanism by which a zinc finger protein can recognize mCpG sites as well as a specific, nonmethylated regulatory DNA sequence.protein-DNA interaction | NMR spectroscopy | X-ray crystallography | folding upon binding | intrinsic disorder I n eukaryotes, DNA methylation is a common epigenetic modification that is central to the maintenance of genome stability, gene silencing, genomic imprinting, development, and disease (1, 2). Methyl-CpG-binding proteins (MBPs) mediate these processes by binding to methylated DNA signals and recruiting chromatin remodeling corepressor complexes, resulting in compaction of chromatin into its transcriptionally inactive state (3). To date, three classes of MBPs that recognize 5-methyl cytosine (5mC) have been identified. The SRA domain family has specificity for hemimethylated sites and is required for maintenance methylation during DNA replication (4). In contrast, the methyl CpG-binding domain (MBD) and Kaiso families of MBPs function as essential mediators of epigenetically controlled gene silencing by recognizing symmetrically methylated CpG sites (5). Kaiso is a MBP belonging to the BTB/POZ (broad complex, tramtrak, bric à brac/pox virus and zinc finger) subfamily of transcription factors that recognize cognate DNA sequences through a C-terminal zinc finger domain; the N-terminal BTB/POZ domain mediates protein-protein interactions (6). Kaiso is a POZ protein that participates in both methyl-dependent and sequence-specific transcriptional repression, using its three Cys 2 His 2 zinc fingers to recognize either two consecutive symmetrically methylated CpG dinucleotides (mCpG) (7, 8) or a TCCTGCNA consensus (termed "KBS") (9). Although originally it was reported that Kaiso only requires zinc fingers 2 and 3 for DNA recog...

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Kaiso-Deficient Mice Show Resistance to Intestinal Cancer

Cited by 145 publications

References 49 publications

A SILAC-based DNA protein interaction screen that identifies candidate binding proteins to functional DNA elements

A SILAC-based DNA protein interaction screen that identifies candidate binding proteins to functional DNA elements

Proteins that bind methylated DNA and human cancer: reading the wrong words

Molecular basis for recognition of methylated and specific DNA sequences by the zinc finger protein Kaiso

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