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Structural and Functional Aspects of DNA Polymerases

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (1 July 2019) | Viewed by 8593

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Special Issue Information

Dear Colleagues,

During the process of DNA replication, DNA polymerases add mononucleotides into a growing primer using a DNA or RNA template to guide each incorporation event. While conceptually simple, this process is remarkably challenging due to the structural diversity in DNA and nucleotide substrates as well as in the number of DNA polymerases that are involved in the cellular replication of nuclear and mitochondrial DNA. In this Special Issue, we have asked international experts in this field to use their expertise to provide novel insights into the mechanism and structure of these important and enigmatic enzymes. The topics of this Special Issue include discussions on our current understanding of how high- and low-fidelity DNA polymerases replicate both normal and damaged DNA. Additional areas of interest focus on drug development, specifically toward generating potent and selective therapeutic agents against DNA polymerases involved in cancer and viral/bacterial infections. Finally, several articles will focus on current and emerging biotechnical methodologies including PCR and genomic sequencing. Collectively, this Special Issue will provide an outstanding collection of work highlighting the key principles in catalysis and fidelity of DNA polymerases, as well as how mutagenesis and pathological conditions can arise from defects in fidelity.

Prof. Anthony J. Berdis
Guest Editor

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Keywords

DNA polymerases
fidelity
mutagenesis
translesion DNA synthesis
nucleotide analogs
DNA sequencing
anti-cancer agents
anti-viral agents
polymerase chain reaction

Published Papers (2 papers)

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Research

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15 pages, 2244 KiB

Open AccessArticle

Probing the Effect of Bulky Lesion-Induced Replication Fork Conformational Heterogeneity Using 4-Aminobiphenyl-Modified DNA

by Ang Cai, Ke Bian, Fangyi Chen, Qi Tang, Rachel Carley, Deyu Li and Bongsup P. Cho

Molecules 2019, 24(8), 1566; https://doi.org/10.3390/molecules24081566 - 20 Apr 2019

Cited by 3 | Viewed by 2351

Abstract

Bulky organic carcinogens are activated in vivo and subsequently react with nucleobases of cellular DNA to produce adducts. Some of these DNA adducts exist in multiple conformations that are slowly interconverted to one another. Different conformations have been implicated in different mutagenic and repair outcomes. However, studies on the conformation-specific inhibition of replication, which is more relevant to cell survival, are scarce, presumably due to the structural dynamics of DNA lesions at the replication fork. It is difficult to capture the exact nature of replication inhibition by existing end-point assays, which usually detect either the ensemble of consequences of all the conformers or the culmination of all cellular behaviors, such as mutagenicity or survival rate. We previously reported very unusual sequence-dependent conformational heterogeneities involving FABP-modified DNA under different sequence contexts (TG₁*G₂T [67%B:33%S] and TG₁G₂*T [100%B], G*, N-(2′-deoxyguanosin-8-yl)-4′-fluoro-4-aminobiphenyl) (Cai et al. Nucleic Acids Research, 46, 6356–6370 (2018)). In the present study, we attempted to correlate the in vitro inhibition of polymerase activity to different conformations from a single FABP-modified DNA lesion. We utilized a combination of surface plasmon resonance (SPR) and HPLC-based steady-state kinetics to reveal the differences in terms of binding affinity and inhibition with polymerase between these two conformers (67%B:33%S and 100%B). Full article

(This article belongs to the Special Issue Structural and Functional Aspects of DNA Polymerases)

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Review

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20 pages, 1133 KiB

Open AccessReview

Mammalian DNA Polymerase Kappa Activity and Specificity

by Hannah R. Stern, Jana Sefcikova, Victoria E. Chaparro and Penny J. Beuning

Molecules 2019, 24(15), 2805; https://doi.org/10.3390/molecules24152805 - 01 Aug 2019

Cited by 21 | Viewed by 5877

Abstract

DNA polymerase (pol) kappa is a Y-family translesion DNA polymerase conserved throughout all domains of life. Pol kappa is special6 ized for the ability to copy DNA containing minor groove DNA adducts, especially N²-dG adducts, as well as to extend primer termini containing DNA damage or mismatched base pairs. Pol kappa generally cannot copy DNA containing major groove modifications or UV-induced photoproducts. Pol kappa can also copy structured or non-B-form DNA, such as microsatellite DNA, common fragile sites, and DNA containing G quadruplexes. Thus, pol kappa has roles both in maintaining and compromising genomic integrity. The expression of pol kappa is altered in several different cancer types, which can lead to genome instability. In addition, many cancer-associated single-nucleotide polymorphisms have been reported in the POLK gene, some of which are associated with poor survival and altered chemotherapy response. Because of this, identifying inhibitors of pol kappa is an active area of research. This review will address these activities of pol kappa, with a focus on lesion bypass and cellular mutagenesis. Full article

(This article belongs to the Special Issue Structural and Functional Aspects of DNA Polymerases)

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