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Papers by Marc Bentele

Research paper thumbnail of Uracil Repair - A Source of DNA Glycosylase Dependent Genome Instability

ABSTRACTUracil DNA glycosylases (UDGs) excise uracil from DNA arising from dUMP misincorporation ... more ABSTRACTUracil DNA glycosylases (UDGs) excise uracil from DNA arising from dUMP misincorporation during replication or from cytosine deamination. Besides functioning in canonical uracil repair, UDGs cooperate with DNA base modifying enzymes to effect mutagenesis or DNA demethylation. Mammalian cells express four UDGs, the functional dissection of which represents a challenge. Here, we usedSchizosaccharomyces pombewith only two UDGs, Ung1 and Thp1, as a simpler model to study functional interactions in uracil repair. We show that despite a predominance of Ung1 activity in cell extracts, both UDGs act redundantly against genomic uracil accumulation and mutations from cytosine deamination in cells. Notably, Thp1 but not Ung1-dependent repair is cytotoxic under genomic uracil stress induced by 5-fluorouracil exposure or AID expression. Also, Thp1-but not Ung1-mediated base excision is recombinogenic, accounting for more than 60% of spontaneous mitotic recombination events in a recombina...

Research paper thumbnail of The versatile thymine DNA-glycosylase: a comparative characterization of the human, Drosophila and ®ssion yeast orthologs

Human thymine-DNA glycosylase (TDG) is well known to excise thymine and uracil from G´T and G´U m... more Human thymine-DNA glycosylase (TDG) is well known to excise thymine and uracil from G´T and G´U mismatches, respectively, and was therefore proposed to play a central role in the cellular defense against genetic mutation through spon-taneous deamination of 5-methylcytosine and cyto-sine. In this study, we characterized two newly discovered orthologs of TDG, the Drosophila melanogaster Thd1p and the Schizosaccharomyces pombe Thp1p proteins, with an objective to address the function of this subfamily of uracil-DNA glycosylases from an evolutionary perspective. A systematic biochemical comparison of both enzymes with human TDG revealed a number of biologically signi®cant facts. (i) All eukaryotic TDG orthologs have broad and species-speci®c substrate spectra that include a variety of damaged pyrimidine and purine bases; (ii) the common most ef®ciently processed substrates of all are uracil and 3,N4-ethenocytosine opposite guanine and 5-¯uorouracil in any double-stranded DNA context; (i...

Research paper thumbnail of The role of uracil repair in the maintenance of genome stability in fission yeast

Research paper thumbnail of PMD16 - Health Economic Evaluation of an Ultrathin, Bioresorbable Polymer Sirolimus-Eluting Coronary Stent Compared to a Thin, Durable Polymer Everolimus-Eluting Stent

Research paper thumbnail of Cost and mortality implications of lower event rates after implantation of an ultrathin strut coronary stent compared with a thin strut stent over four years

Cardiovascular Revascularization Medicine

Research paper thumbnail of Two-Year Results After Implantation of an Ultrathin, Bioresorbable Polymer Sirolimus-Eluting Coronary Stent Compared to a Thin, Durable Polymer Everolimus-Eluting Stent: Health Economic Evaluation

Journal of the American College of Cardiology

Research paper thumbnail of 100.63 Health Economic Evaluation of the Two-Year Results After Implantation of an Ultrathin, Bioresorbable-Polymer Sirolimus-Eluting Coronary Stent Compared to a Thin, Durable-Polymer Everolimus-Eluting Stent

JACC: Cardiovascular Interventions

Research paper thumbnail of Health Economic Evaluation of an Ultrathin, Bioresorbable Polymer Sirolimus-Eluting Coronary Stent Compared to a Thin, Durable Polymer Everolimus-Eluting Stent

Cardiovascular Revascularization Medicine

Research paper thumbnail of The versatile thymine DNA-glycosylase: a comparative characterization of the human, Drosophila and fission yeast orthologs

Nucleic Acids Research, 2003

Human thymine-DNA glycosylase (TDG) is well known to excise thymine and uracil from G´T and G´U m... more Human thymine-DNA glycosylase (TDG) is well known to excise thymine and uracil from G´T and G´U mismatches, respectively, and was therefore proposed to play a central role in the cellular defense against genetic mutation through spontaneous deamination of 5-methylcytosine and cytosine. In this study, we characterized two newly discovered orthologs of TDG, the Drosophila melanogaster Thd1p and the Schizosaccharomyces pombe Thp1p proteins, with an objective to address the function of this subfamily of uracil-DNA glycosylases from an evolutionary perspective. A systematic biochemical comparison of both enzymes with human TDG revealed a number of biologically signi®cant facts. (i) All eukaryotic TDG orthologs have broad and species-speci®c substrate spectra that include a variety of damaged pyrimidine and purine bases; (ii) the common most ef®ciently processed substrates of all are uracil and 3,N4ethenocytosine opposite guanine and 5-¯uorouracil in any double-stranded DNA context; (iii) 5-methylcytosine and thymine derivatives are processed with an appreciable ef®ciency only by the human and the Drosophila enzymes; (iv) none of the proteins is able to hydrolyze a non-damaged 5¢-methylcytosine opposite G; and (v) the double strand and mismatch dependency of the enzymes varies with the substrate and is not a stringent feature of this subfamily of DNA glycosylases. These ®ndings advance our current view on the role of TDG proteins and document that they have evolved with high structural exibility to counter a broad range of DNA base damage in accordance with the speci®c needs of individual species.

Research paper thumbnail of Separating Substrate Recognition from Base Hydrolysis in Human Thymine DNA Glycosylase by Mutational Analysis

Journal of Biological Chemistry, 2000

Research paper thumbnail of Separating Substrate Recognition from Base Hydrolysis in Human Thymine DNA Glycosylase by Mutational Analysis

Journal of Biological Chemistry, 2000

Research paper thumbnail of NEJ1 controls non-homologous end joining in Saccharomyces cerevisiae

Research paper thumbnail of Uracil Repair - A Source of DNA Glycosylase Dependent Genome Instability

ABSTRACTUracil DNA glycosylases (UDGs) excise uracil from DNA arising from dUMP misincorporation ... more ABSTRACTUracil DNA glycosylases (UDGs) excise uracil from DNA arising from dUMP misincorporation during replication or from cytosine deamination. Besides functioning in canonical uracil repair, UDGs cooperate with DNA base modifying enzymes to effect mutagenesis or DNA demethylation. Mammalian cells express four UDGs, the functional dissection of which represents a challenge. Here, we usedSchizosaccharomyces pombewith only two UDGs, Ung1 and Thp1, as a simpler model to study functional interactions in uracil repair. We show that despite a predominance of Ung1 activity in cell extracts, both UDGs act redundantly against genomic uracil accumulation and mutations from cytosine deamination in cells. Notably, Thp1 but not Ung1-dependent repair is cytotoxic under genomic uracil stress induced by 5-fluorouracil exposure or AID expression. Also, Thp1-but not Ung1-mediated base excision is recombinogenic, accounting for more than 60% of spontaneous mitotic recombination events in a recombina...

Research paper thumbnail of The versatile thymine DNA-glycosylase: a comparative characterization of the human, Drosophila and ®ssion yeast orthologs

Human thymine-DNA glycosylase (TDG) is well known to excise thymine and uracil from G´T and G´U m... more Human thymine-DNA glycosylase (TDG) is well known to excise thymine and uracil from G´T and G´U mismatches, respectively, and was therefore proposed to play a central role in the cellular defense against genetic mutation through spon-taneous deamination of 5-methylcytosine and cyto-sine. In this study, we characterized two newly discovered orthologs of TDG, the Drosophila melanogaster Thd1p and the Schizosaccharomyces pombe Thp1p proteins, with an objective to address the function of this subfamily of uracil-DNA glycosylases from an evolutionary perspective. A systematic biochemical comparison of both enzymes with human TDG revealed a number of biologically signi®cant facts. (i) All eukaryotic TDG orthologs have broad and species-speci®c substrate spectra that include a variety of damaged pyrimidine and purine bases; (ii) the common most ef®ciently processed substrates of all are uracil and 3,N4-ethenocytosine opposite guanine and 5-¯uorouracil in any double-stranded DNA context; (i...

Research paper thumbnail of The role of uracil repair in the maintenance of genome stability in fission yeast

Research paper thumbnail of PMD16 - Health Economic Evaluation of an Ultrathin, Bioresorbable Polymer Sirolimus-Eluting Coronary Stent Compared to a Thin, Durable Polymer Everolimus-Eluting Stent

Research paper thumbnail of Cost and mortality implications of lower event rates after implantation of an ultrathin strut coronary stent compared with a thin strut stent over four years

Cardiovascular Revascularization Medicine

Research paper thumbnail of Two-Year Results After Implantation of an Ultrathin, Bioresorbable Polymer Sirolimus-Eluting Coronary Stent Compared to a Thin, Durable Polymer Everolimus-Eluting Stent: Health Economic Evaluation

Journal of the American College of Cardiology

Research paper thumbnail of 100.63 Health Economic Evaluation of the Two-Year Results After Implantation of an Ultrathin, Bioresorbable-Polymer Sirolimus-Eluting Coronary Stent Compared to a Thin, Durable-Polymer Everolimus-Eluting Stent

JACC: Cardiovascular Interventions

Research paper thumbnail of Health Economic Evaluation of an Ultrathin, Bioresorbable Polymer Sirolimus-Eluting Coronary Stent Compared to a Thin, Durable Polymer Everolimus-Eluting Stent

Cardiovascular Revascularization Medicine

Research paper thumbnail of The versatile thymine DNA-glycosylase: a comparative characterization of the human, Drosophila and fission yeast orthologs

Nucleic Acids Research, 2003

Human thymine-DNA glycosylase (TDG) is well known to excise thymine and uracil from G´T and G´U m... more Human thymine-DNA glycosylase (TDG) is well known to excise thymine and uracil from G´T and G´U mismatches, respectively, and was therefore proposed to play a central role in the cellular defense against genetic mutation through spontaneous deamination of 5-methylcytosine and cytosine. In this study, we characterized two newly discovered orthologs of TDG, the Drosophila melanogaster Thd1p and the Schizosaccharomyces pombe Thp1p proteins, with an objective to address the function of this subfamily of uracil-DNA glycosylases from an evolutionary perspective. A systematic biochemical comparison of both enzymes with human TDG revealed a number of biologically signi®cant facts. (i) All eukaryotic TDG orthologs have broad and species-speci®c substrate spectra that include a variety of damaged pyrimidine and purine bases; (ii) the common most ef®ciently processed substrates of all are uracil and 3,N4ethenocytosine opposite guanine and 5-¯uorouracil in any double-stranded DNA context; (iii) 5-methylcytosine and thymine derivatives are processed with an appreciable ef®ciency only by the human and the Drosophila enzymes; (iv) none of the proteins is able to hydrolyze a non-damaged 5¢-methylcytosine opposite G; and (v) the double strand and mismatch dependency of the enzymes varies with the substrate and is not a stringent feature of this subfamily of DNA glycosylases. These ®ndings advance our current view on the role of TDG proteins and document that they have evolved with high structural exibility to counter a broad range of DNA base damage in accordance with the speci®c needs of individual species.

Research paper thumbnail of Separating Substrate Recognition from Base Hydrolysis in Human Thymine DNA Glycosylase by Mutational Analysis

Journal of Biological Chemistry, 2000

Research paper thumbnail of Separating Substrate Recognition from Base Hydrolysis in Human Thymine DNA Glycosylase by Mutational Analysis

Journal of Biological Chemistry, 2000

Research paper thumbnail of NEJ1 controls non-homologous end joining in Saccharomyces cerevisiae

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