The C-Terminal Domain of the Adenine-DNA Glycosylase MutY Confers Specificity for 8-Oxoguanine·Adenine Mispairs and May Have Evolved from MutT, an 8-Oxo-dGTPase

Noll, David M.; Gogos, Arhonda; Granek, Joshua A.; Clarke, Neil D.

doi:10.1021/bi990335x

Cited by 106 publications

(139 citation statements)

References 36 publications

(46 reference statements)

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“…Over a short reaction period the rate of cleavage of calf mtMYH was much faster for the A/8-oxoG mismatch than other substrates. This substrate reactivity is similar to that of E.coli MutY (2,57,58). In view of the fact that mitochondrial OGG1-like protein will cleave 8-oxoG-containing mismatches and not mismatches paired with G, it is of biological importance that mtMYH binds tightly to A/8-oxoG mismatches but not A/G or A/C mismatches.…”

Section: Discussionsupporting

confidence: 53%

Purification and characterization of a mammalian homolog of Escherichia coli MutY mismatch repair protein from calf liver mitochondria

Parker

2000

Nucleic Acids Research

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A protein homologous to the Escherichia coli MutY glycosylase, referred to as mtMYH, has been purified from calf liver mitochondria. SDS-polyacrylamide gel electrophoresis, western blot analysis as well as gel filtration chromatography predicted the molecular mass of the purified calf mtMYH to be 35-40 kDa. Gel mobility shift analysis showed that the purified mtMYH formed specific binding complexes with A/8-oxoG, G/8-oxoG and T/8-oxoG, weakly with C/8-oxoG, but not with A/G and A/C mismatches. The purified mtMYH exhibited DNA glycosylase activity removing adenine mispaired with G, C or 8-oxoG and weakly removing guanine mispaired with 8-oxoG. The mtMYH glycosylase activity was insensitive to high concentrations of NaCl and EDTA. The purified mtMYH cross-reacted with antibodies against both intact MutY and a peptide of human MutY homolog (hMYH). DNA glycosylase activity of mtMYH was inhibited by anti-MutY antibodies but not by antihMYH peptide antibodies. Together with the previously described mitochondrial MutT homolog (MTH1) and 8-oxoG glycosylase (OGG1, a functional MutM homolog), mtMYH can protect mitochondrial DNA from the mutagenic effects of 8-oxoG.

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Section: Discussionsupporting

confidence: 53%

Purification and characterization of a mammalian homolog of Escherichia coli MutY mismatch repair protein from calf liver mitochondria

Parker

2000

Nucleic Acids Research

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“…The C-terminal domain has sequence (58) and structural homology to the d(OG)TPase MutT (59), indicating a role in recognition of OG. Kinetic experiments with substrates and binding assays with substrate analogs are consistent with a role of the C-terminal domain in OG recognition and nucleotide flipping (58,60). However, it is possible that this domain has additional functions.…”

supporting

confidence: 60%

“…A-containing DNA-We (60) and others (58,67) have previously shown that removal of the C-terminal domain to form a truncated enzyme (henceforth referred to as Stop 225) affects the intrinsic rate for adenine removal. However, Stop 225 retains biphasic kinetic behavior under conditions of substrate excess, indicating that the rate of product release remains rate-limiting in a manner similar to that observed with the WT enzyme (60).…”

Section: Endo IV Does Not Significantly Increase the Product Release mentioning

confidence: 99%

Escherichia coli Apurinic-Apyrimidinic Endonucleases Enhance the Turnover of the Adenine Glycosylase MutY with G:A Substrates

Pope¹,

Porello

David

2002

Journal of Biological Chemistry

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The DNA repair enzyme MutY plays an important role in the prevention of DNA mutations resulting from the presence of the oxidatively damaged lesion 7,8-dihydro-8-oxo-2-deoxyguanosine (OG). MutY is a base excision repair (BER) glycosylase that removes misincorporated adenine residues from OG:A mispairs, as well as G:A and C:A mispairs. We have previously shown that, under conditions of low MutY concentrations relative to an OG:A or G:A substrate, the time course of the adenine glycosylase reaction exhibits biphasic kinetic behavior due to slow release of the DNA product by MutY. The dissociation of MutY from its product may require the recruitment of other proteins from the BER pathway, such as an apurinic-apyrimidinic (AP) endonuclease, as turnover-enhancing cofactors. The effect of the AP endonucleases endonuclease IV (Endo IV), exonuclease III (Exo III), and Ape1 on the reaction kinetics of MutY with G:A-and OG:A-containing substrates was investigated. The effect of the glycosylases UDG and MutM and the DNA polymerase pol I was also characterized. Endo IV and Exo III, unlike Ape1, UDG, and pol I, greatly enhance the rate of product release with a G:A substrate, whereas the rate constant for the adenine removal step remains unchanged. Furthermore, the turnover rate with a truncated form of MutY, Stop 225, which lacks 125 amino acids of the C terminus, is unaffected by the presence of Endo IV or Exo III. These results constitute the first evidence of an interaction between the MutY-product DNA complex and Endo IV or Exo III. Furthermore, they suggest a role for the C-terminal domain of MutY in mediating this interaction. The base excision repair (BER)1 pathway is the primary cellular mechanism charged with the task of removing DNA bases modified via hydrolysis, oxidation, and alkylation (1). BER relies on the action of damage-specific DNA glycosylases that recognize various types of modified or inappropriate bases within the context of normal Watson-Crick DNA (2). The repair process is initiated by hydrolytic removal of the target base by the relevant DNA glycosylase and proceeds by incision at the abasic site, generation of a gap, reparative DNA synthesis, and ligation of the nicked DNA (1, 3). The BER pathway has been reconstituted in vitro with cell-free extracts or purified protein components, and these experiments have established the minimal requirements for restoration of the damaged DNA (4 -11). For example, repair of uracil in DNA was achieved by use of five Escherichia coli proteins: uracil-DNA glycosylase (UDG), endonuclease IV (an AP endonuclease), RecJ protein, DNA polymerase I, and DNA ligase (7). Both "short patch" and "long patch" BER pathways have been observed, which differ in the number of nucleotides and the various protein components involved (12, 13). The type of BER pathway utilized depends on the organism and the type of DNA damage; however, minimally the BER pathway requires a damage-specific glycosylase, an AP endonuclease, DNA polymerase, and DNA ligase.The DNA glycosylases of BER may ...

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“…The N-terminal domain of E. coli MutY has the catalytic activity (36 -40); however, the C-terminal domain is important for GO recognition (36,37,40,41). The PCNA binding motifs located at the Cterminal ends of eukaryotic MYH are not conserved in bacterial MutY proteins.…”

Section: The Interactions Between Myh and Pcna Proteins From Both S mentioning

confidence: 99%

Functional Interaction of MutY Homolog with Proliferating Cell Nuclear Antigen in Fission Yeast, Schizosaccharomyces pombe

Chang

2002

Journal of Biological Chemistry

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The MutY homolog (MYH) is responsible for removing adenines misincorporated on a template DNA strand containing G or 7,8-dihydro-8-oxoguanine (8-oxoG) and thus preventing G:C to T:A mutations. Human MYH has been shown to interact physically with human proliferating cell nuclear antigen (hPCNA). Here, we report that a similar interaction between SpMYH and SpPCNA occurs in the fission yeast Schizosaccharomyces pombe. Binding of SpMYH to

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The C-Terminal Domain of the Adenine-DNA Glycosylase MutY Confers Specificity for 8-Oxoguanine·Adenine Mispairs and May Have Evolved from MutT, an 8-Oxo-dGTPase

Cited by 106 publications

References 36 publications

Purification and characterization of a mammalian homolog of Escherichia coli MutY mismatch repair protein from calf liver mitochondria

Purification and characterization of a mammalian homolog of Escherichia coli MutY mismatch repair protein from calf liver mitochondria

Escherichia coli Apurinic-Apyrimidinic Endonucleases Enhance the Turnover of the Adenine Glycosylase MutY with G:A Substrates

Functional Interaction of MutY Homolog with Proliferating Cell Nuclear Antigen in Fission Yeast, Schizosaccharomyces pombe

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