Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.30.2 (endonuclease)
 18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CpG methylation, the most common epigenetic modification of vertebrate genomes, is primarily associated with transcriptional repression. MeCP2, MBD1, MBD2, MBD3 and MBD4 constitute a family of vertebrate proteins that share the methyl-CpG-binding domain (MBD). The MBD, consisting of about 70 residues, possesses a unique alpha/beta-sandwich structure with characteristic loops, and is able to bind single methylated CpG pairs as a monomer. All MBDs except MBD4, an endonuclease that forms a complex with the DNA mismatch-repair protein MLH1, form complexes with histone deacetylase. It has been established that MeCP2, MBD1 and MBD2 are involved in histone deacetylase-dependent repression and it is likely that this is also the case for MBD3. The current model proposes that MBD proteins are involved in recruiting histone deacetylases to methyl CpG-enriched regions in the genome to repress transcription. The lack of selectivity for MBD association with particular DNA sequences indicates that other mechanisms account for their recruitment to particular regions in the genome.
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PMID:Methyl-CpG-binding proteins. Targeting specific gene repression. 1112 Oct 95

Epigenome modifications of the human genome play an important role in gene expression regulation and chromatin structure formation. Methylation of cytosine of the CpG dinucleotides is one of the main epigenone modifications of the human genome. Changes in the CpG-islands methylation status of tumor-suppressing genes and oncogenes play an important role in carcinogenesis. Determination of DNA methylation status in oncology is important for early tumor diagnostics, choice and monitoring of cancer treatment and prognosis of survival of patients with cancer after surgeries. There is a wide range of approaches to determination of DNA methylation status now. The review purpose is to characterize main approaches to the determination of the CpG dinucleotides methylation status, which could be used in oncology. They include: bisulfite sequencing, bisulfite pyrosequencing, MS-REA (methylation-sensitive restriction endonuclease assay), MSP (methylation-specific PCR), COBRA (combined bisulfite restriction analysis), MS-SnuPE (methylation-sensitive single nucleotide primer extension), MS-SSCA (methylation-sensitive single-strand conformation analysis), MethyLight, HeavyMethyl, MALDI-TOF MS (matrix-assisted laser desorption/ionization time-to-flight mass spectrometry), FMCA (fluorescence melting curve analysis), restriction genome scanning, use of microarrays for determining genes with increased expression after DNA methylation inhibition, DMH (differential methylation hybridization), use of capability of methylCpG-binding domain of MeCP2 protein to bind methylated DNA, immunoprecipitation of methylated DNA with antibodies specific for methylated cytosines. A general principle, advantages, disadvantages and potential artifacts here been described for each approach in the paper.
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PMID:[Modern methodical approaches to determining the DNA methylation status and their use in oncology]. 1914 Apr 45

Neural progenitor cells undergo somatic retrotransposition events, mainly involving L1 elements, which can be potentially deleterious. Here, we analyze the whole genomes of 20 brain samples and 80 non-brain samples, and characterized the retrotransposition landscape of patients affected by a variety of neurodevelopmental disorders including Rett syndrome, tuberous sclerosis, ataxia-telangiectasia and autism. We report that the number of retrotranspositions in brain tissues is higher than that observed in non-brain samples and even higher in pathologic vs normal brains. The majority of somatic brain retrotransposons integrate into pre-existing repetitive elements, preferentially A/T rich L1 sequences, resulting in nested insertions. Our findings document the fingerprints of encoded endonuclease independent mechanisms in the majority of L1 brain insertion events. The insertions are "non-classical" in that they are truncated at both ends, integrate in the same orientation as the host element, and their target sequences are enriched with a CCATT motif in contrast to the classical endonuclease motif of most other retrotranspositions. We show that L1Hs elements integrate preferentially into genes associated with neural functions and diseases. We propose that pre-existing retrotransposons act as "lightning rods" for novel insertions, which may give fine modulation of gene expression while safeguarding from deleterious events. Overwhelmingly uncontrolled retrotransposition may breach this safeguard mechanism and increase the risk of harmful mutagenesis in neurodevelopmental disorders.
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PMID:Whole-genome sequencing reveals principles of brain retrotransposition in neurodevelopmental disorders. 2932 25

The RNA-guided endonuclease Cas9 can be converted into a programmable transcriptional repressor, but inefficiencies in target-gene silencing have limited its utility. Here we describe an improved Cas9 repressor based on the C-terminal fusion of a rationally designed bipartite repressor domain, KRAB-MeCP2, to nuclease-dead Cas9. We demonstrate the system's superiority in silencing coding and noncoding genes, simultaneously repressing a series of target genes, improving the results of single and dual guide RNA library screens, and enabling new architectures of synthetic genetic circuits.
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PMID:An enhanced CRISPR repressor for targeted mammalian gene regulation. 3001 45

Mutations in X-linked methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome (RTT). To identify functional pathways that could inform therapeutic entry points, we carried out a genetic screen for secondary mutations that improved phenotypes in Mecp2/Y mice after mutagenesis with N-ethyl-N-nitrosourea (ENU). Here, we report the isolation of 106 founder animals that show suppression of Mecp2-null traits from screening 3177 Mecp2/Y genomes. Whole-exome sequencing, genetic crosses, and association analysis identified 22 candidate genes. Additional lesions in these candidate genes or pathway components associate variant alleles with phenotypic improvement in 30 lines. A network analysis shows that 63% of the genes cluster into the functional categories of transcriptional repression, chromatin modification, or DNA repair, delineating a pathway relationship with MECP2. Many mutations lie in genes that modulate synaptic signaling or lipid homeostasis. Mutations in genes that function in the DNA damage response (DDR) also improve phenotypes in Mecp2/Y mice. Association analysis was successful in resolving combinatorial effects of multiple loci. One line, which carries a suppressor mutation in a gene required for cholesterol synthesis, Sqle, carries a second mutation in retinoblastoma binding protein 8, endonuclease (Rbbp8, also known as CtIP), which regulates a DDR choice in double-stranded break (DSB) repair. Cells from Mecp2/Y mice have increased DSBs, so this finding suggests that the balance between homology-directed repair and nonhomologous end joining is important for neuronal cells. In this and other lines, two suppressor mutations confer greater improvement than one alone, suggesting that combination therapies could be effective in RTT.
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PMID:Suppressor mutations in Mecp2-null mice implicate the DNA damage response in Rett syndrome pathology. 3231 54