DNA mismatch correction is a strand-specific process involving recognition of noncomplementary Watson-Crick nucleotide pairs and participation of widely separated DNA sites. The Escherichia coli methyl-directed reaction has been reconstituted in a purified system consisting of MutH, MutL, and MutS proteins, DNA helicase II, single-strand DNA binding protein, DNA polymerase III holoenzyme, exonuclease I, DNA ligase, along with ATP (adenosine triphosphate), and the four deoxynucleoside triphosphates. This set of proteins can process seven of the eight base-base mismatches in a strand-specific reaction that is directed by the state of methylation of a single d(GATC) sequence located 1 kilobase from the mispair.
"Studies using bacteria and yeast uncovered MMR as a long patch correction system and identified its protein components (Grilley et al., 1990). The MMR process was then reconstituted using bacterial (Lahue et al., 1989), yeast (Bowen et al., 2013), and mammalian proteins (Constantin et al., 2005; Zhang et al., 2005). Defects in this pathway were shown to give rise to a mutator phenotype in bacteria and yeast with characteristic traits at repetitive sequences of simple nature, microsatellites (microsatellite instability, MSI; Levinson and Gutman, 1987; Strand et al., 1993). "
[Show abstract][Hide abstract] ABSTRACT: DNA is constantly under attack by a number of both exogenous and endogenous agents that challenge its integrity. Among the mechanisms that have evolved to counteract this deleterious action, mismatch repair (MMR) has specialized in removing DNA biosynthetic errors that occur when replicating the genome. Malfunction or inactivation of this system results in an increase in spontaneous mutability and a strong predisposition to tumor development. Besides this key corrective role, MMR proteins are involved in other pathways of DNA metabolism such as mitotic and meiotic recombination and processing of oxidative damage. Surprisingly, MMR is also required for certain mutagenic processes. The mutagenic MMR has beneficial consequences contributing to the generation of a vast repertoire of antibodies through class switch recombination and somatic hypermutation processes. However, this non-canonical mutagenic MMR also has detrimental effects; it promotes repeat expansions associated with neuromuscular and neurodegenerative diseases and may contribute to cancer/disease-related aberrant mutations and translocations. The reaction responsible for replication error correction has been the most thoroughly studied and it is the subject to numerous reviews. This review describes briefly the biochemistry of MMR and focuses primarily on the non-canonical MMR activities described in mammals as well as emerging research implicating interplay of MMR and chromatin.
Frontiers in Genetics 08/2014; 5:287. DOI:10.3389/fgene.2014.00287
"It was demonstrated that transient hemimethylation of adenine in 5'-GATC-3' sequences is involved in DNA strand discrimination during mutHLS-dependent mismatch repair (Bakker & Smith, 1989; Barras & Marinus, 1989; Lahue et al. 1989, Modrich, 1989). Additionally it was suggested that this mechanism has a pivotal role in the initiation of DNA replication of E. coli, because the 245 bp oriC sequence contains a high abundance of GATC motifs (eleven at all) and fully methylated it is twice as active in comparison to the unmethylated state (Barras & Marinus, 1988; Boye, 1991). "
[Show abstract][Hide abstract] ABSTRACT: Epigenetic modification plays a dual role in bacterial infection. On the one hand, the expression of cer- tain genes in the bacterial organism is regulated by epigenetic mechanisms. For example, the expression of components of the type IV secretion system in Gram-negative bacteria like enteroaggregative Esche- richia coli (EAggEC), which is responsible for the secretion of proteins involved in host cell invasion and bacterial killing, is regulated by DNA methylation (Brunet et al., 2011).
Differences in the digestion-pattern of endonucleases recognizing methylated adenine at 5’- GATC-3’-sites in the genomes of several Gram-negative bacterial species like Campylobacter coli (Wright et al., 2010) and Campylobacter jejuni (Gu et al., 2009) suggest that further genes are regulated by epigenetic modifications as well.
Bioinformatic investigations demonstrated epigenetic regulation of type III secretion system (TTSS) associated toxicity in the non-fermentative Gram-negative facultative pathogen Pseudomonas aeruginosa (Filopon et al., 2006). A generalized logical analysis indicated epigenetic control of Pseudo- monas aeruginosa’s mucoidy (Guespin-Michel & Kaufman, 2001). There are even hints for epigenetic regulation of multistationary of bacterial growth (Guespin-Michel & Kaufman, 2001).
On the other hand, bacterial infections induce epigenetic changes in the cells of the infected organ- ism. It is a well described phenomenon that viral proteins affect the activity of cellular promoters via epi- genetic mechanisms. In the last years similar effects were demonstrated for bacterial infections. Promotor silencing by hypermethylation at CpG dinucleotides was described for Campylobacter rectus in placenta tissue (Bobetsis et al., 2007) and for Helicobacter pylori in gastric mucosa (Chan et al., 2003). This epi- genetic reprogramming might play a critical role in fetal growth and ontogenetic programming but also in carcinogenesis.
In contrast, methylation of bacterial 16S rRNA is a resistance mechanism providing high-level re- sistance to aminoglycosides in actinomycetes, Enterobacteriaceae and Gram-negative, non-fementing, rod-shaped bacteria like Pseudomonas aeruginosa (Yokoyama et al., 2003; Doi et al., 2004; Périchon et al., 2008). However, this phenomenon is no epigenetic mechanism as gene expression is not affected.
Infection with Gram-negativ bacteria induces epigenetic modifications not only in the invading bacterial cells, but also in the host tissue. Epigenetic consequences of bacterial infection are important for the understanding of the pathomechanisms and may have principal therapeutic implications.
Introduction to Genetics: DNA Methylation, Histone Modification and Gene Regulation, 1st edited by Jun Wan, 07/2013: chapter Epigenetic Modifications in Gram-Negative Bacteria and the Induction of Patho-Epigenetic Modifications in Host Tissue: pages 270; iConcept Press., ISBN: 978-1477554944
"In all systems, following mismatch or IDL detection by a MutS homologue, MutL (MutLa or MutLb in eukaryotes) is recruited to the site of the mismatch in a reaction that requires ATP (Schofield et al., 2001b). Following this step, MutL is hypothesized to facilitate removal of the mismatch by co-ordinating numerous DNA transactions including endonuclease nicking, helicase-driven unwinding and excision of the segment containing the misincorporated base(s) (Lahue et al., 1989). unstructured region of MutS (MutS800) containing a putative DnaN clamp-binding motif, reduced interaction with DnaN, yet MutS800 maintained the ability to preferentially bind mismatched DNA in vitro (Simmons et al., 2008). "
[Show abstract][Hide abstract] ABSTRACT: Mismatch repair (MMR) increases the fidelity of DNA replication by identifying and correcting replication errors. Processivity clamps are vital components of DNA replication and MMR, yet the mechanism and extent to which they participate in MMR remains unclear. We investigated the role of the Bacillus subtilis processivity clamp DnaN, and found that it serves as a platform for mismatch detection and coupling of repair to DNA replication. By visualizing functional MutS fluorescent fusions in vivo, we find that MutS forms foci independent of mismatch detection at sites of replication (i.e. the replisome). These MutS foci are directed to the replisome by DnaN clamp zones that aid mismatch detection by targeting the search to nascent DNA. Following mismatch detection, MutS disengages from the replisome, facilitating repair. We tested the functional importance of DnaN-mediated mismatch detection for MMR, and found that it accounts for 90% of repair. This high dependence on DnaN can be bypassed by increasing MutS concentration within the cell, indicating a secondary mode of detection in vivo whereby MutS directly finds mismatches without associating with the replisome. Overall, our results provide new insight into the mechanism by which DnaN couples mismatch recognition to DNA replication in living cells.
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