Direct Reversal of DNA Alkylation Damage

Department of Chemistry, University of Chicago, Chicago, Illinois, United States
Chemical Reviews (Impact Factor: 46.57). 03/2006; 106(2):215-32. DOI: 10.1021/cr0404702
Source: PubMed


A review of three direct dealkylation repair protein families of N-Ada, O6-alkylguanine-DNA alkyltransferase, and AlkB is presented. Focus is on the chemical aspects of these repair functions as well as on the recent advances made toward understanding the structure, function, and mechanism of these proteins. Inhibition of AGT (hAGT) as a potential strategy to improve the efficacy of anticancer alkylation chemotherapies is discussed, as well as recent strageties to utilize this protein for in vivo imaging and protein-immobilization applications.

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    • "Indeed, it was previously reported that S. solfataricus shows sensitivity to UV radiation doses comparable to that of Escherichia coli (Salerno et al. 2003; Romano et al. 2007), whereas it was very sensitive to lower doses of the alkylating agent MMS (Valenti et al. 2006, 2009). DNA alkyltransferases (called AGT, MGMT or OGT) are small (17–20 kDa) proteins conserved in most (although not all) eukaryotes, bacteria and archaea, that catalyze repair of DNA alkylation damage (mainly at the O6 position of guanine) by a one-step mechanism involving the transfer of the alkylic group from DNA to a cysteine residue in the protein active site (reviewed in Mishina et al. 2006; Tubbs et al. 2007; Pegg 2011). This reaction results in direct repair of DNA, but also irreversible alkylation and inactivation of the protein. "
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    ABSTRACT: Repair and defence of genome integrity from endogenous and environmental hazard is a primary need for all organisms. Natural selection has driven the evolution of multiple cell pathways to deal with different DNA damaging agents. Failure of such processes can hamper cell functions and induce inheritable mutations, which in humans may cause cancerogenicity or certain genetic syndromes, and ultimately cell death. A special case is that of hyperthermophilic bacteria and archaea, flourishing at temperatures higher than 80 °C, conditions that favor genome instability and thus call for specific, highly efficient or peculiar mechanisms to keep their genome intact and functional. Over the last few years, numerous studies have been performed on the activity, function, regulation, physical and functional interaction of enzymes and proteins from hyperthermophilic microorganisms that are able to bind, repair, bypass damaged DNA, or modify its structure or conformation. The present review is focused on two enzymes that act on DNA catalyzing unique reactions: reverse gyrase and DNA alkyltransferase. Although both enzymes belong to evolutionary highly conserved protein families present in organisms of the three domains (Eucarya, Bacteria and Archaea), recently characterized members from hyperthermophilic archaea show both common and peculiar features.
    Extremophiles 08/2014; 18(5). DOI:10.1007/s00792-014-0662-9 · 2.31 Impact Factor
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    • "DDR pathways are also unique in that they involve only one type of protein, meaning that one protein has to be able to fulfill all the tasks, it has to find the damage, verify it, and remove it. DDR pathways are only available for very few select types of DNA lesions; in humans, direct repair mechanisms are limited to a subset of base-alkylation products [1] [2] [3]. DNA alkylation is highly mutagenic and cytotoxic and ubiquitously occurs, for instance, through natural endogenous alkylating agents [4] [5]. "
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    ABSTRACT: The O6-alkylguanine DNA alkyltransferase (AGT) is a highly conserved protein responsible for direct repair of alkylated guanine and to a lesser degree thymine bases. While specific DNA lesion-bound complexes in crystal structures consist of monomeric AGT, several solution studies have suggested that cooperative DNA binding plays a role in the physiological activities of AGT. Cooperative AGT–DNA complexes have been described by theoretical models, which can be tested by atomic force microscopy (AFM). Direct access to structural features of AGT–DNA complexes at the single molecule level by AFM imaging revealed non-specifically bound, cooperative complexes with limited cluster length. Implications of cooperative binding in AGT–DNA interactions are discussed.
    DNA repair 08/2014; 20. DOI:10.1016/j.dnarep.2014.01.006 · 3.11 Impact Factor
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    • "R) motif is highly conserved in all AlkB family members, and the five invariant residues are essential for enzymatic activity [32]. Usually, the second arginine is considered as an a-KG-binding residue, but our structure of DfALKBH5 shows a potential weaker interaction between Arg251 and a-KG. "
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    ABSTRACT: ALKBH5, a member of AlkB family proteins, has been reported as a mammalian N(6)-methyladenosine (m(6)A) RNA demethylase. Here we report the crystal structure of zebrafish ALKBH5 (fALKBH5) with the resolution of 1.65 Å. Structural superimposition shows that fALKBH5 is comprised of a conserved jelly-roll motif. However, it possesses a loop that interferes potential binding of a duplex nucleic acid substrate, suggesting an important role in substrate selection. In addition, several active site residues are different between the two known m(6)A RNA demethylases, ALKBH5 and FTO, which may result in their slightly different pathways of m(6)A demethylation.
    FEBS letters 02/2014; 588(6). DOI:10.1016/j.febslet.2014.02.021 · 3.17 Impact Factor
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