Mismatch dependent uracil/thymine-DNA glycosylases excise exocyclic hydroxyethano and hydroxypropano cytosine adducts.

• Authors: Ewa Borys-Brzywczy , Katarzyna D Arczewska , Murat Saparbaev , Ulrike Hardeland , Primo Schär , Jarosław T Kuśmierek
• Languages of publication: EN

Abstracts

EN

Exocyclic adducts of DNA bases, such as etheno- and hydroxyalkano- ones, are generated by a variety of bifunctional agents, including endogenously formed products of lipid peroxidation. In this work we selectively modified cytosines in the 5'-d(TTT TTT CTT TTT CTT TTT CTT TTT T)-3' oligonucleotide using: chloroacetaldehyde to obtain 3,N4-α-hydroxyethano- (HEC) and 3,N4-etheno- (εC), acrolein to obtain 3,N4-α-hydroxypropano- (HPC) and crotonaldehyde to obtain 3,N4-α-hydroxy-γ-methylpropano- (mHPC) adducts of cytosine. The studied adducts are alkali-labile which results in oligonucleotide strain breaks at the sites of modification upon strong base treatment. The oligonucleotides carrying adducted cytosines were studied as substrates of Escherichia coli Mug, human TDG and fission yeast Thp1p glycosylases. All the adducts studied are excised by bacterial Mug although with various efficiency: εC >HEC >HPC >mHPC. The yeast enzyme excises efficiently εC ł HEC >HPC, whereas the human enzyme excises only εC. The pH-dependence curves of excision of εC, HEC and HPC by Mug are bell shaped and the most efficient excision of adducts occurs within the pH range of 8.6-9.6. The observed increase of excision of HEC and HPC above pH 7.2 can be explained by deprotonation of these adducts, which are high pKa compounds and exist in a protonated form at neutrality. On the other hand, since εC is in a neutral form in the pH range studied, we postulate an involvement of an additional catalytic factor. We hypothesize that the enzyme structure undergoes a pH-induced rearrangement allowing the participation of Lys68 of Mug in catalysis via a hydrogen bond interaction of its ε-amino group with N4 of the cytosine exocyclic adducts.

Keywords

EN

base excision repair; E. coli mismatch uracil-DNA glycosylase; exocyclic cytosine adducts; human thymine-DNA glycosylase; S. pombe Thp1p glycosylase

• Publisher: Polish Biochemical Society
• Journal: Acta Biochimica Polonica
• Year: 2005
• Volume: 52
• Issue: 1
• Pages: 149-165

Dates

published

2005

received

2004-11-19

accepted

2005-03-03

Contributors

author

Ewa Borys-Brzywczy

• Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warszawa, Poland

author

Katarzyna D Arczewska

• Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warszawa, Poland

author

Murat Saparbaev

• Groupe "Réparation de l'ADN", UMR 8532 CNRS, Institut Gustave Roussy, Villejuif, Cedex, France

author

Ulrike Hardeland

• Biochemie-Zentrum-Heidelberg, University of Heidelberg, Heidelberg, Germany

author

Primo Schär

• Institute of Biochemistry and Genetics, University of Basel, Basel, Switzerland

author

Jarosław T Kuśmierek

• Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warszawa, Poland

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