Repair of oxidative DNA damage |
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Authors: | A-Lien Lu Xianghong Li Yesong Gu Patrick M Wright Dau-Yin Chang |
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Institution: | (1) Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, 21201 Baltimore, MD |
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Abstract: | Cellular genomes suffer extensive damage from exogenous agents and reactive oxygen species formed during normal metabolism.
The MutT homologs (MutT/MTH) remove oxidized nucleotide precursors so that they cannot be incorporated into DNA during replication.
Among many repair pathways, the base excision repair (BER) pathway is the most important cellular protection mechanism responding
to oxidative DNA damage. The 8-oxoG glycosylases (Fpg or MutM/OGG) and the MutY homologs (MutY/MYH) glycosylases along with
MutT/MTH protect cells from the mutagenic effects of 8-oxoG, the most stable and deleterious product known caused by oxidative
damage to DNA. The key enzymes in the BER process are DNA glycosylases, which remove different damaged bases by cleavage of
the N-glycosylic bonds between the bases and the deoxyribose moieties of the nucleotide residues. Biochemical and structural studies
have demonstrated the substrate recognition and reaction mechanism of BER enzymes. Cocrystal structures of strated the substrate
recognition and reaction mechanism of BER enzymes. Cocrystal structures of several glycosylases show that the substrate base
flips out of the sharply bent DNA helix and the minor groove is widened to be accessed by the glycosylases. To complete the
repair after glycosylase action, the apurinic/apyrimidinic (AP) site is further processed by an incision step, DNA synthesis,
an excision step, and DNA ligation through two alternative pathways. The short-patch BER (1-nucleotide patch size) and long-patch
BER (2–6-nucleotide patch size) pathways need AP endonuclease to generate a 3′ hydroxyl group but require different sets of
enzymes for DNA synthesis and ligation. Protein-protein interactions have been reported among the enzymes involved in BER.
It is possible that the successive players in the repair pathway are assembled in a complex to perform concerted actions.
The BER pathways are proposed to protect cells and organisms from mutagenesis and carcinogenesis. |
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Keywords: | Oxidative DNA damage mutagenesis DNA base excision repair DNA glycosylase MutY MutM MutT endonuclease III AP lyase AP endonuclease enzyme mechanism structure and function |
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