Modulation of the activity of methyl binding domain protein 4 (MBD4/MED1) while processing iododeoxyuridine generated DNA mispairs

Aziz, Mehar; Schupp, Jane E.; Kinsella, Timothy J.

doi:10.4161/cbt.8.12.8536

Cited by 12 publications

(4 citation statements)

References 32 publications

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“…MBD4 is active on several halogenated pyrimidines, including 5-chlorouracil and 5-bromouracil paired with G that result from peroxidase-mediated inflammatory processes [20,21], as well as chemotherapy-induced 5-fluorouracil (5-FU) and 5-iododeoxyuracil lesions [22,23]. Furthermore, MBD4 exhibits weak glycosylase activity on 3,N 4 -ethenocytosine (εC), a product of lipid peroxidation and metabolite of vinyl chloride and ethyl carbamate [18].…”

Section: Substrates Of Mbd4mentioning

confidence: 99%

MBD4 and TDG: Multifaceted DNA glycosylases with ever expanding biological roles

Sjolund

Senejani

Sweasy

2013

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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The base excision repair system is vital to the repair of endogenous and exogenous DNA damage. This pathway is initiated by one of several DNA glycosylases that recognizes and excises specific DNA lesions in a coordinated fashion. Methyl-CpG Domain Protein 4 (MBD4) and Thymine DNA Glycosylase (TDG) are the two major G:T glycosylases that remove thymine generated by the deamination of 5-methylcytosine. Both of these glycosylase also remove a variety of other base lesions, including G:U and preferentially act at CpG sites throughout the genome. Many have questioned the purpose of seemingly redundant glycosylases, but new information has emerged to suggest MBD4 and TDG have diverse biological functions. MBD4 has been closely linked to apoptosis, while TDG has been clearly implicated in transcriptional regulation. This article reviews all these developments, and discusses the consequences of germline and somatic mutations that lead to non-synonymous amino acid substitutions on MBD4 and TDG protein function. In addition, we report the finding of alternately spliced variants of MBD4 and TDG and the results of functional studies of a tumor-associated variant of MBD4.

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Section: Substrates Of Mbd4mentioning

confidence: 99%

MBD4 and TDG: Multifaceted DNA glycosylases with ever expanding biological roles

Sjolund

Senejani

Sweasy

2013

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…It has been suggested that this truncated form of MBD4 acts in a dominant negative way, competitively inhibiting normal glycosylase activity of wild type MBD4, and increasing the mutation frequency when over-expressed in cells [107-109]. Inhibition of TDG (thymine DNA glycosylase) activity m5CG/GIU by the MBD domain was not observed [110]. This indicates the MBD domain possess an additional role in at least regulating MBD4 glycosylase activity, in addition to binding meCpGs and mismatched sites.…”

Section: Mbd4 Apoptosis and Mis-match Repairmentioning

confidence: 99%

Apoptosis and DNA Methylation

Meng

Nestor

Dunican

et al. 2011

Cancers

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Epigenetic mechanisms assist in maintaining gene expression patterns and cellular properties in developing and adult tissues. The molecular pathology of disease states frequently includes perturbation of DNA and histone methylation patterns, which can activate apoptotic pathways associated with maintenance of genome integrity. This perspective focuses on the pathways linking DNA methyltransferases and methyl-CpG binding proteins to apoptosis, and includes new bioinformatic analyses to characterize the evolutionary origin of two G/T mismatch-specific thymine DNA glycosylases, MBD4 and TDG.

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“…The MBD4 GD markedly distorts the DNA backbone which likely inhibits simultaneous binding with the MBD4 MBD (4,8). The isolated MBD4 GD maintains enzymatic activity in isolation while addition of free MBD4 MBD inhibits activity towards a single m CpG/TpG mismatch site (9). MBD4 GD orthologs in invertebrates frequently lack an associated MBD (Supplementary Table S1), again supporting the observation that the MBD4 GD does not require a MBD for function.…”

Section: Introductionmentioning

confidence: 99%

Solution structure and intramolecular exchange of methyl-cytosine binding domain protein 4 (MBD4) on DNA suggests a mechanism to scan for mCpG/TpG mismatches

Walavalkar¹,

Cramer²,

Buchwald³

et al. 2014

Nucleic Acids Research

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Unlike other members of the methyl-cytosine binding domain (MBD) family, MBD4 serves as a potent DNA glycosylase in DNA mismatch repair specifically targeting mCpG/TpG mismatches arising from spontaneous deamination of methyl-cytosine. The protein contains an N-terminal MBD (MBD4MBD) and a C-terminal glycosylase domain (MBD4GD) separated by a long linker. This arrangement suggests that the MBD4MBD either directly augments enzymatic catalysis by the MBD4GD or targets the protein to regions enriched for mCpG/TpG mismatches. Here we present structural and dynamic studies of MBD4MBD bound to dsDNA. We show that MBD4MBD binds with a modest preference formCpG as compared to mismatch, unmethylated and hydroxymethylated DNA. We find that while MBD4MBD exhibits slow exchange between molecules of DNA (intermolecular exchange), the domain exhibits fast exchange between two sites in the same molecule of dsDNA (intramolecular exchange). Introducing a single-strand defect between binding sites does not greatly reduce the intramolecular exchange rate, consistent with a local hopping mechanism for moving along the DNA. These results support a model in which the MBD4MBD4 targets the intact protein to mCpG islands and promotes scanning by rapidly exchanging between successive mCpG sites which facilitates repair of nearby mCpG/TpG mismatches by the glycosylase domain.

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Modulation of the activity of methyl binding domain protein 4 (MBD4/MED1) while processing iododeoxyuridine generated DNA mispairs

Cited by 12 publications

References 32 publications

MBD4 and TDG: Multifaceted DNA glycosylases with ever expanding biological roles

MBD4 and TDG: Multifaceted DNA glycosylases with ever expanding biological roles

Apoptosis and DNA Methylation

Solution structure and intramolecular exchange of methyl-cytosine binding domain protein 4 (MBD4) on DNA suggests a mechanism to scan for mCpG/TpG mismatches

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