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      O6-2′-Deoxyguanosine-butylene-O6-2′-deoxyguanosine DNA Interstrand Cross-Links Are Replication-Blocking and Mutagenic DNA Lesions

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          Abstract

          <p class="first" id="P1">DNA interstrand cross-links (ICLs) are cytotoxic DNA lesions derived from reactions of DNA with a number of anti-cancer reagents as well as endogenous bifunctional electrophiles. Deciphering the DNA repair mechanisms of ICLs is important for understanding the toxicity of DNA cross-linking agents and for developing effective chemotherapies. Previous research has focused on ICLs cross-linked with the N7 and N2 atoms of guanine as well as those formed at the N6 atom of adenine; however, little is known about the mutagenicity of <i>O</i> <sup>6</sup>-dG-derived ICLs. Although less abundant, <i>O</i> <sup>6</sup>-alkylated guanine DNA lesions are chemically stable and highly mutagenic. Here, <i>O</i> <sup>6</sup>-2′-deoxyguanosine-butylene- <i>O</i> <sup>6</sup>-2′-deoxyguanosine ( <i>O</i> <sup>6</sup>-dG-C4- <i>O</i> <sup>6</sup>-dG) is designed as a chemically stable ICL, which can be induced by the action of bifunctional alkylating agents. We investigate the DNA replication-blocking and mutagenic properties of <i>O</i> <sup>6</sup>-dG-C4- <i>O</i> <sup>6</sup>-dG ICLs during an important step in ICL repair, translesion DNA synthesis (TLS). The model replicative DNA polymerase (pol) <i>Sulfolobus solfataricus</i> P2 DNA polymerase B1 (Dpo1) is able to incorporate a correct nucleotide opposite the cross-linked template guanine of ICLs with low efficiency and fidelity but cannot extend beyond the ICLs. Translesion synthesis by human pol <i>κ</i> is completely inhibited by <i>O</i> <sup>6</sup>-dG-C4- <i>O</i> <sup>6</sup>-dG ICLs. Moderate bypass activities are observed for human pol <i>η</i> and <i>S. solfataricus</i> P2 DNA polymerase IV (Dpo4). Among the pols tested, pol <i>η</i> exhibits the highest bypass activity; however, 70% of the bypass products are mutagenic containing substitutions or deletions. The increase in the size of unhooked repair intermediates elevates the frequency of deletion mutation. Lastly, the importance of pol <i>η</i> in <i>O</i> <sup>6</sup>-dG-derived ICL bypass is demonstrated using whole cell extracts of Xeroderma pigmentosum variant patient cells and those complemented with pol <i>η</i>. Together, this study provides the first set of biochemical evidence for the mutagenicity of <i>O</i> <sup>6</sup>-dG-derived ICLs. </p><p id="P2"> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/0ff22c58-651a-4e6b-8daf-dda4a68ab337/PubMedCentral/image/nihms892524u1.jpg"/> </div> </p>

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          Author and article information

          Journal
          Chemical Research in Toxicology
          Chem. Res. Toxicol.
          American Chemical Society (ACS)
          0893-228X
          1520-5010
          October 21 2016
          November 21 2016
          November 04 2016
          November 21 2016
          : 29
          : 11
          : 1872-1882
          Affiliations
          [1 ]Department of Chemistry and Biochemistry, Concordia University, 7141 Sherbrooke Street West, Montréal, Québec H4B 1R6, Canada
          [2 ]Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, United States
          Article
          10.1021/acs.chemrestox.6b00278
          5665164
          27768841
          11cdbb5d-dddc-4db8-b49f-f253dfb06bd3
          © 2016
          History

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