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Title: Uncovering the polymerase-induced cytotoxicity of an oxidized nucleotide

Abstract

Oxidative stress promotes genomic instability and human diseases. A common oxidized nucleoside is 8-oxo-7,8-dihydro-2’-deoxyguanosine found both in DNA (8-oxo-G) and as a free nucleotide (8-oxo-dGTP). Nucleotide pools are especially vulnerable to oxidative damage. Therefore cells encode an enzyme (MutT/MTH1) that removes free oxidized nucleotides. This cleansing function is required for cancer cell survival and to modulate E. coli antibiotic sensitivity in a DNA polymerase (pol)-dependent manner. How polymerase discriminates between damaged and non-damaged nucleotides is not well understood. This analysis is essential given the role of oxidized nucleotides in mutagenesis, cancer therapeutics, and bacterial antibiotics. Even with cellular sanitizing activities, nucleotide pools contain enough 8-oxo-dGTP to promote mutagenesis. This arises from the dual coding potential where 8-oxo-dGTP(anti) base pairs with cytosine (Cy) and 8-oxodGTP(syn) utilizes its Hoogsteen edge to base pair with adenine (Ad). Here in this paper we utilized time-lapse crystallography to follow 8-oxo-dGTP insertion opposite Ad or Cy with human DNA pol β, to reveal that insertion is accommodated in either the syn- or anti-conformation, respectively. For 8-oxo-dGTP(anti) insertion, a novel divalent metal relieves repulsive interactions between the adducted guanine base and the triphosphate of the oxidized nucleotide. With either templating base, hydrogen bonding interactions between the basesmore » are lost as the enzyme reopens after catalysis, leading to a cytotoxic nicked DNA repair intermediate. Combining structural snapshots with kinetic and computational analysis reveals how 8-oxodGTP utilizes charge modulation during insertion that can lead to a blocked DNA repair intermediate.« less

Authors:
 [1];  [1];  [1];  [1];  [2];  [3];  [1]
+ Show Author Affiliations
  1. National Inst. of Environmental Health Sciences (NIEHS), Research Triangle Park, NC (United States). Lab. of Structural Biology
  2. New York Univ. (NYU), NY (United States). Courant Inst. of Mathematical Sciences, Dept. of Chemistry
  3. New York Univ. (NYU), NY (United States). Courant Inst. of Mathematical Sciences, Dept. of Chemistry
Publication Date:
Research Org.:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH)
OSTI Identifier:
1168869
Grant/Contract Number:  
W-31-109-Eng-38; 1U19CA105010
Resource Type:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 517; Journal Issue: 7536; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; 60 APPLIED LIFE SCIENCES; DNA; Cancer; X-ray crystallography

Citation Formats

Freudenthal, Bret D., Beard, William A., Perera, Lalith, Shock, David D., Kim, Taejin, Schlick, Tamar, and Wilson, Samuel H. Uncovering the polymerase-induced cytotoxicity of an oxidized nucleotide. United States: N. p., 2014. Web. doi:10.1038/nature13886.
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Freudenthal, Bret D., Beard, William A., Perera, Lalith, Shock, David D., Kim, Taejin, Schlick, Tamar, & Wilson, Samuel H. Uncovering the polymerase-induced cytotoxicity of an oxidized nucleotide. United States. https://doi.org/10.1038/nature13886
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Freudenthal, Bret D., Beard, William A., Perera, Lalith, Shock, David D., Kim, Taejin, Schlick, Tamar, and Wilson, Samuel H. Mon . "Uncovering the polymerase-induced cytotoxicity of an oxidized nucleotide". United States. https://doi.org/10.1038/nature13886. https://www.osti.gov/servlets/purl/1168869.
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@article{osti_1168869,
title = {Uncovering the polymerase-induced cytotoxicity of an oxidized nucleotide},
author = {Freudenthal, Bret D. and Beard, William A. and Perera, Lalith and Shock, David D. and Kim, Taejin and Schlick, Tamar and Wilson, Samuel H.},
abstractNote = {Oxidative stress promotes genomic instability and human diseases. A common oxidized nucleoside is 8-oxo-7,8-dihydro-2’-deoxyguanosine found both in DNA (8-oxo-G) and as a free nucleotide (8-oxo-dGTP). Nucleotide pools are especially vulnerable to oxidative damage. Therefore cells encode an enzyme (MutT/MTH1) that removes free oxidized nucleotides. This cleansing function is required for cancer cell survival and to modulate E. coli antibiotic sensitivity in a DNA polymerase (pol)-dependent manner. How polymerase discriminates between damaged and non-damaged nucleotides is not well understood. This analysis is essential given the role of oxidized nucleotides in mutagenesis, cancer therapeutics, and bacterial antibiotics. Even with cellular sanitizing activities, nucleotide pools contain enough 8-oxo-dGTP to promote mutagenesis. This arises from the dual coding potential where 8-oxo-dGTP(anti) base pairs with cytosine (Cy) and 8-oxodGTP(syn) utilizes its Hoogsteen edge to base pair with adenine (Ad). Here in this paper we utilized time-lapse crystallography to follow 8-oxo-dGTP insertion opposite Ad or Cy with human DNA pol β, to reveal that insertion is accommodated in either the syn- or anti-conformation, respectively. For 8-oxo-dGTP(anti) insertion, a novel divalent metal relieves repulsive interactions between the adducted guanine base and the triphosphate of the oxidized nucleotide. With either templating base, hydrogen bonding interactions between the bases are lost as the enzyme reopens after catalysis, leading to a cytotoxic nicked DNA repair intermediate. Combining structural snapshots with kinetic and computational analysis reveals how 8-oxodGTP utilizes charge modulation during insertion that can lead to a blocked DNA repair intermediate.},
doi = {10.1038/nature13886},
journal = {Nature (London)},
number = 7536,
volume = 517,
place = {United States},
year = {Mon Nov 17 00:00:00 EST 2014},
month = {Mon Nov 17 00:00:00 EST 2014}
}
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Mutagenic conformation of 8-oxo-7,8-dihydro-2′-dGTP in the confines of a DNA polymerase active site
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