Editorial Cite This: Chem. Res. Toxicol. 2017, 30, 1921-1921
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DNA Polymerases: From Molecular Mechanisms to Human Disease, a Special Issue his issue of Chemical Research in Toxicology is dedicated to DNA polymerases, which are enzymes that play a central role in maintaining the integrity of genetic information. These molecular machines carry out numerous DNA transactions including priming DNA synthesis, carrying out high-efficiency replication, and engaging in DNA repair and DNA damage tolerance. The discovery of specialized DNA polymerases that have the ability to replicate damaged DNA or other noncanonical DNA structures can provide an explanation for DNA damage tolerance and DNA damage-induced mutagenesis. DNA polymerases can also be harnessed for biotechnology applications related to toxicology, for example, in the detection of DNA damage. In addition, many aspects of DNA replication are targeted by anticancer therapies. Because of the ability of some DNA polymerases to replicate damaged DNA and to tolerate other DNA replication stresses, DNA polymerases and more generally DNA replication are attractive drug targets. Thus, the field of DNA polymerases is vast and multifaceted. The collection of research, review, and perspective articles in this special issue represents examples of current topics of high interest primarily related to the molecular details of how DNA polymerases interact with the DNA damage results of toxicant exposure as well as DNA polymerases as drug targets. Several articles are focused on the roles of DNA polymerases in tumor progression and as drug targets for antiviral or anticancer chemotherapies. Tumors in particular are often characterized by genome instability and replication stress and specialized DNA polymerases can both contribute to and help alleviate this instability and stress. Moreover, many cancer chemotherapy agents damage DNA and inhibit cell division as their mechanisms of action. Inhibiting damage-bypass DNA polymerases is likely to be a fruitful strategy to improve cellular responses to chemotherapy. In addition, understanding the mechanisms of incorporation of therapeutic nucleoside analogs by DNA polymerases is likely to lead to improved therapies and is discussed in this special issue. Other current topics that address major issues in the field include the basic mechanisms of damage bypass by specialized DNA polymerases as well as how cells regulate polymerase access to DNA. Structural biology, computational chemistry, protein engineering, and single-molecule biophysics approaches are all presented in this special issue to provide new insights into the mechanisms by which DNA polymerases help cells tolerate DNA damage. Beyond the paradigm of a single polymerase acting to bypass DNA damage, the regulation of DNA polymerase access to DNA and coordination of multiple DNA polymerases in cells are still important open questions in the field, and models considering organized protein complexes or switching via polymerase exchange are presented here. These reports probe the roles of a number of DNA polymerases in replicating DNA containing different types of damage and provide insights into DNA damage tolerance and potential mechanisms of mutagenesis. These articles also
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advance the possibility of targeting DNA polymerases with pharmaceutical agents in cancer chemotherapy and highlight molecular features of DNA polymerase regulation. Thus, the topics presented in this special issue focus on some of the major current issues in the DNA polymerase field, which it is hoped will inspire DNA polymerase researchers to consider new approaches and other systems to address these challenges.
Penny J. Beuning*
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Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Phone: 617-373-2865. ORCID
Penny J. Beuning: 0000-0002-7770-022X Notes
Views expressed in this editorial are those of the author and not necessarily the views of the ACS.
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ACKNOWLEDGMENTS This issue was made possible by the authors, reviewers, and editorial staff who generously gave their time, energy, and ideas. Their contributions are gratefully acknowledged.
Special Issue: DNA Polymerases: From Molecular Mechanisms to Human Disease Published: November 20, 2017 1921
DOI: 10.1021/acs.chemrestox.7b00261 Chem. Res. Toxicol. 2017, 30, 1921−1921
