DNA polymerases provide a canon of strategies for translesion synthesis past oxidatively generated lesions

Department of Microbiology and Molecular Genetics, The Markey Center for Molecular Genetics, University of Vermont, Burlington, VT 05405, USA.
Current Opinion in Structural Biology (Impact Factor: 7.2). 06/2011; 21(3):358-69. DOI: 10.1016/
Source: PubMed


Deducing the structure of the DNA double helix in 1953 implied the mode of its replication: Watson-Crick (WC) base pairing might instruct an enzyme, now known as the DNA polymerase, during the synthesis of a daughter stand complementary to a single strand of the parental double helix. What has become increasingly clear in the last 60 years, however, is that adducted and oxidatively generated DNA bases are ubiquitous in physiological DNA, and all organisms conserve multiple DNA polymerases specialized for DNA synthesis opposite these damaged templates. Here, we review recent crystal structures depicting replicative and bypass DNA polymerases encountering two typical lesions arising from the oxidation of DNA: abasic sites, which block the replication fork, and the miscoding premutagenic lesion 7,8-dihydro-8-oxoguanine (8-oxoG).

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    • "But surprisingly, it is also used by translesion polymerases. Eukaryotic pol ζ (or REV3L) is a 353 kDa polymerase which functions in translesion synthesis and appears to suppress tumorigenesis (Wittschieben et al., 2010; Lange et al., 2011; Zahn et al., 2011; Hogg and Johansson, 2012; Sharma et al., 2013). The structure of E. coli Pol II revealed modifications in the NTD which affect the position of the β hairpin of the exonuclease domain, and thus partitioning of the DNA between the polymerization and proofreading sites (Wang and Yang, 2009). "
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    Frontiers in Microbiology 08/2014; 5:444. DOI:10.3389/fmicb.2014.00444 · 3.99 Impact Factor
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    • "The above mentioned mechanism can be operative in various organisms that involve the CPDs or (6-4) PPs correction process [14]. The DNA repair process has also been reviewed in [15], where the crystal structures of the replicative and bypass DNA polymerases were encountered. Thereby two typical lesions arising from the oxidation of DNA were distinguished. "
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    The Open Biochemistry Journal 03/2014; 8(1):35-43. DOI:10.2174/1874091X01408010035
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    • "Environmental and Molecular Mutagenesis. DOI 10.1002/em unrepaired lesions [for reviews, see Hogg et al., 2005; Zahn et al., 2011], as well as defining the consequences of individual lesions in terms of potential lethality and/or mutagenesis [for a review, see Wallace, 2002]. In this review, we focus on how structure provides insights into function using the Fpg/Nei family of DNA glycosylases as an example and as well how the DNA glycosylases search for their substrates in DNA. "
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    ABSTRACT: This review article presents, an overview of the DNA glycosylases that recognize oxidized DNA bases using the Fpg/Nei family of DNA glycosylases as models for how structure can inform function. For example, even though human NEIL1 and the plant and fungal orthologs lack the zinc finger shown to be required for binding, DNA crystal structures revealed a "zincless finger" with the same properties. Moreover, the "lesion recognition loop" is not involved in lesion recognition, rather, it stabilizes 8-oxoG in the active site pocket. Unlike the other Fpg/Nei family members, Neil3 lacks two of the three void-filling residues that stabilize the DNA duplex and interact with the opposite strand to the damage which may account for its preference for lesions in single-stranded DNA. Also single-molecule approaches show that DNA glycosylases search for their substrates in a sea of undamaged DNA by using a wedge residue that is inserted into the DNA helix to probe for the presence of damage. Environ. Mol. Mutagen., 2013. © 2013 Wiley Periodicals, Inc.
    Environmental and Molecular Mutagenesis 12/2013; 54(9). DOI:10.1002/em.21820 · 2.63 Impact Factor
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