Mechanisms in Eukaryotic Mismatch Repair

ArticleinJournal of Biological Chemistry 281(41):30305-9 · November 2006with17 Reads
DOI: 10.1074/jbc.R600022200 · Source: PubMed
    • "The system presented here accords with the theory that the genetic code is itself shaped by natural selection [5] [6] [7], and that its evolution [8] [9] alongside the DNA mutation repair system [10] [11] and tRNA translation mechanism [12] has produced a table with the adaptive benefit [13] [14] that single-nucleotide mutations [15] most likely to cause a loss of protein function are also the most likely to be avoided [16] or fixed. Ancestral versions of the genetic code may have already exhibited clustering of related amino acids as a result of stereochemical or biosynthetic similarities [17]. "
    [Show abstract] [Hide abstract] ABSTRACT: This article introduces a novel binary representation of the canonical genetic code, in which each of the four mRNA nucleotide bases is assigned a unique 2-bit identifier. These designations have a physiological meaning derived from the molecular structures of, and relationships between, the bases. In this scheme, the 64 possible triplet codons are each indexed by a 6-bit label. The order of the bits reflects the hierarchical organization manifested by the DNA replication/repair and tRNA translation systems. Transition and transversion mutations are naturally expressed as basic binary operations, and the severity of the different types is analyzed. Using a principal component analysis, it is shown that physicochemical properties of amino acids related to protein folding also correlate with particular bit positions of their respective labels. Thus, the likelihood for a particular point mutation to be conservative, and therefore less likely to cause a change in protein functionality, can be estimated.
    Article · Jul 2016 · Critical Reviews in Biochemistry and Molecular Biology
    • "MSH6 also has a unique N-terminal disordered domain that is absent in its MSH2 partner. The hMutSα heterodimer binds to DNA mispairs and short insertion deletion loops (IDLs) [13,[60][61][62][63][64]. Mutations of MSH6 gene had been reported to be associated with many cancers but mainly with HNPCC syndrome, and to date the exact mechanism of how these mutations promote tumor genesis remains controversial, in the present study we presented a computational analysis for the reported MSH6 SNPs using several public softwares and databases in an attempt to understand how do these mutations affect the protein structure and function and hence promote a disease. "
    [Show abstract] [Hide abstract] ABSTRACT: Background: Point mutations in MSH6 gene had been related to group of cancers called lynch syndrome which accounts for 3% to 5% of all colorectal cancers. Despite the excessively studied MSH6 mutations, the mechanism by which these mutations promote carcinogenesis remains controversial. Methods: MSH6 was investigated in dbSNP/NCBI in December 2015, 3666 SNPs were found in human; 388 were coding synonymous, 937 non synonymous, 201 in frame shift, 63 in 3' un-translated region and 347 in 5' un-translated region. Non synonymous and 3'UTR SNPs were selected for insilico analysis; SIFT, Polyphen2, Imutant3.0, MUpro, PhD-SNP, SNPs & GO, MutPred, ELASPIC, Mutation 3D, UCSF Chimera 1.8, PolymiRTs, and GENEMAIA softwares and servers were used to investigate the effect of SNPs on MSH6 protein's structure and function. Results: 21 SNPs were found to be highly damaging for the protein by SIFT and Polyphen, and were further analyzed by I-Mutant, MUpro, PHD-SNP, SNPs & GO, ELASPIS, Mutation 3D and Chimera. 2 SNPs were predicted by PolymiRTs to induce disruption or creation of miR binding sites; rs200412142 contained 2 disrupting and 1 creating functional classes in 3 miRSite, while rs184571821 SNP contained 3 creating functional classes in 3 miRSites. GENEMANIA revealed five genes similar in their expression level with MSH6 and seven genes share the same protein domain with it. Conclusions: 14 nsSNPs () were located at the interface of the MSH6 protein interfering with its relation with MSH2ISO2, MSH3, MSH2 and E9PHA6. Interactions of MSH6 with these proteins are critical for its MMR function and any structural alterations that interfere or harm these networks interactions would probably increase susceptibility to tumors formation and progression. 2 SNPs at the 3UTR; rs200412142 and rs184571821 introduced a change in the micro RNA binding site at the 3UT which might result in deregulation of the gene function.
    Full-text · Article · Jul 2016 · Critical Reviews in Biochemistry and Molecular Biology
    • "In vitro, purified Exo1 preferentially degrades dsDNA with a 5 0 recessed end (Cannavo et al., 2013). Exo1 can also degrade from a nick in line with its role in MRX-initiated resection and mismatch repair (Modrich, 2006; Szankasi & Smith, 1992). MRX/N stimulates resection by Exo1 in vitro, even though the genetic studies indicate that Exo1 can function without MRX as long as Ku is absent (Cannavo et al., 2013; Mimitou & Symington, 2010; Nicolette et al., 2010; Nimonkar et al., 2011). "
    [Show abstract] [Hide abstract] ABSTRACT: The repair of DNA double-strand breaks (DSBs) by homologous recombination (HR) is initiated by nucleolytic degradation of the 5'-terminated strands in a process termed end resection. End resection generates 3'-single-stranded DNA tails, substrates for Rad51 to catalyze homologous pairing and DNA strand exchange, and for activation of the DNA damage checkpoint. The commonly accepted view is that end resection occurs by a two-step mechanism. In the first step, Sae2/CtIP activates the Mre11-Rad50-Xrs2/Nbs1 (MRX/N) complex to endonucleolytically cleave the 5'-terminated DNA strands close to break ends, and in the second step Exo1 and/or Dna2 nucleases extend the resected tracts to produce long 3'-ssDNA-tailed intermediates. Initiation of resection commits a cell to repair a DSB by HR because long ssDNA overhangs are poor substrates for non-homologous end joining (NHEJ). Thus, the initiation of end resection has emerged as a critical control point for repair pathway choice. Here, I review recent studies on the mechanism of end resection and how this process is regulated to ensure the most appropriate repair outcome.
    Full-text · Article · Apr 2016
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