Structure and mechanism for DNA lesion recognition

Yang, Wei

doi:10.1038/cr.2007.116

Cited by 122 publications

(119 citation statements)

References 75 publications

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“…However, it was significantly less than that recently reported for 8-oxoguanine DNA glycosylase 1 (OGG1), which requires the involvement of the SWI/SNF chromatin-remodeling complex (44). This result is not surprising, as UNG2, SMUG1, UDG-APE, and MBD4 belong to the same structural family, which is different from that of OGG1 (73).…”

Section: Discussioncontrasting

confidence: 49%

MBD4-Mediated Glycosylase Activity on a Chromatin Template Is Enhanced by Acetylation

Ishibashi

Cupples

et al. 2008

Molecular and Cellular Biology

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The ability of the MBD4 glycosylase to excise a mismatched base from DNA has been assessed in vitro using DNA substrates with different extents of cytosine methylation, in the presence or absence of reconstituted nucleosomes. Despite the enhanced ability of MBD4 to bind to methylated cytosines, the efficiency of its glycosylase activity on T/G mismatches was slightly dependent on the extent of methylation of the DNA substrate. The reduction in activity caused by competitor DNA was likewise unaffected by the methylation status of the substrate or the competitor. Our results also show that MBD4 efficiently processed T/G mismatches within the nucleosome. Furthermore, the glycolytic activity of the enzyme was not affected by the positioning of the mismatch within the nucleosome. However, histone hyperacetylation facilitated the efficiency with which the bases were excised from the nucleosome templates, irrespective of the position of the mismatch relative to the pseudodyad axis of symmetry of the nucleosome.Diverse organisms, prokaryotic and eukaryotic, methylate selected cytosines in their genomes (reviewed by Bestor [19]). In bacteria, methylation is usually associated with restrictionmodification systems which protect the cell against attack from bacteriophages. Cytosine methylation is associated with genome defense in some eukaryotes, but it also plays vital roles in development and in the control of gene expression, to the extent that the homozygous knockout of cytosine methyltransferase genes in the mouse is an embryonic lethal mutation (40). Despite its importance, cytosine methylation imposes a genetic and epigenetic cost because 5-methylcytosines deaminate into thymine (reviewed in references 53 and 67). Unrepaired, the resulting T/G mismatches lead to CG-to-TA transition mutations. There is also evidence from work with Escherichia coli that 5-methylcytosines are more prone to mispairing during DNA replication than unmethylated bases and/or are less well repaired and that they are particularly susceptible to other forms of endogenous and exogenous damage which cause them to mispair (24, 54). A similar situation exists for eukaryotes (reviewed in reference 51).Whatever the cause, mutations at methylated cytosines may influence phenotype in two ways: (i) by introducing nonsense or missense mutations which alter the functions of proteins and (ii) by demethylating promoter regions and thereby altering patterns of gene expression. As one line of defense against the genetic and epigenetic effects of mutations associated with methylated cytosines, cells have developed repair systems specific to T/G mismatches. Cytosine methyltransferases methylate both strands of palindromic recognition sequences (CpG or CNG sequences in eukaryotes and CCWGG sequences in E. coli); consistent with their role in preventing mutations at 5-methylcytosines, the DNA repair systems show a strong preference for T/G mismatches which arise in methylase recognition sequences (31,32,46). E. coli initiates repair with a single-stranded endonuc...

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Section: Discussioncontrasting

confidence: 49%

MBD4-Mediated Glycosylase Activity on a Chromatin Template Is Enhanced by Acetylation

Ishibashi

Cupples

et al. 2008

Molecular and Cellular Biology

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“…The tertiary structure of DNA polymerase is such that the enzyme fits over the previously formed base pairs 1, 2. These bases must be paired correctly for the polymerase to adopt its functional conformation 3, 4, 5…”

Section: Introductionmentioning

confidence: 99%

Single‐molecule mechanochemical characterization of E. coli pol III core catalytic activity

et al. 2017

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Pol III core is the three‐subunit subassembly of the E. coli replicative DNA polymerase III holoenzyme. It contains the catalytic polymerase subunit α, the 3′ → 5′ proofreading exonuclease ε, and a subunit of unknown function, θ. We employ optical tweezers to characterize pol III core activity on a single DNA substrate. We observe polymerization at applied template forces F < 25 pN and exonucleolysis at F > 30 pN. Both polymerization and exonucleolysis occur as a series of short bursts separated by pauses. For polymerization, the initiation rate after pausing is independent of force. In contrast, the exonucleolysis initiation rate depends strongly on force. The measured force and concentration dependence of exonucleolysis initiation fits well to a two‐step reaction scheme in which pol III core binds bimolecularly to the primer‐template junction, then converts at rate k 2 into an exo‐competent conformation. Fits to the force dependence of k init show that exo initiation requires fluctuational opening of two base pairs, in agreement with temperature‐ and mismatch‐dependent bulk biochemical assays. Taken together, our results support a model in which the pol and exo activities of pol III core are effectively independent, and in which recognition of the 3′ end of the primer by either α or ε is governed by the primer stability. Thus, binding to an unstable primer is the primary mechanism for mismatch recognition during proofreading, rather than an alternative model of duplex defect recognition.

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“…However, the bulk of the UV-induced DNA lesionsnot located in the transcribed strand of active genes-are repaired by the GG-NER subpathway of NER. In contrast to TC-NER, damage recognition in GG-NER occurs independent of transcription and requires the concerted action of the XPC/RAD23B and UV-DDB complexes (Gillet and Schärer 2006;Scrima et al 2008;Yang 2008). The further processing of lesions in both TC-NER and GG-NER occurs via a common pathway (Schärer 2011), in which transcription factor TFIIH comes first after the damage is recognized.…”

Section: The Subpathways Of Nermentioning

confidence: 99%

Mammalian Transcription-Coupled Excision Repair

Vermeulen¹,

Fousteri

2013

Cold Spring Harbor Perspectives in Biology

159

118

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Transcriptional arrest caused by DNA damage is detrimental for cells and organisms as it impinges on gene expression and thereby on cell growth and survival. To alleviate transcriptional arrest, cells trigger a transcription-dependent genome surveillance pathway, termed transcription-coupled nucleotide excision repair (TC-NER) that ensures rapid removal of such transcription-impeding DNA lesions and prevents persistent stalling of transcription. Defective TC-NER is causatively linked to Cockayne syndrome, a rare severe genetic disorder with multisystem abnormalities that results in patients' death in early adulthood. Here we review recent data on how damage-arrested transcription is actively coupled to TC-NER in mammals and discuss new emerging models concerning the role of TC-NER-specific factors in this process.

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Structure and mechanism for DNA lesion recognition

Cited by 122 publications

References 75 publications

MBD4-Mediated Glycosylase Activity on a Chromatin Template Is Enhanced by Acetylation

MBD4-Mediated Glycosylase Activity on a Chromatin Template Is Enhanced by Acetylation

Single‐molecule mechanochemical characterization of E. coli pol III core catalytic activity

Mammalian Transcription-Coupled Excision Repair

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