Promutagenicity of 8-Chloroguanine, A Major Inflammation-Induced Halogenated DNA Lesion

Published on 2019in Molecules3.06
· DOI :10.3390/molecules24193507
Yi Kou5
Estimated H-index: 5
Myong-Chul Koag2
Estimated H-index: 2
Seongmin Lee13
Estimated H-index: 13
Chronic inflammation is closely associated with cancer development. One possible mechanism for inflammation-induced carcinogenesis is DNA damage caused by reactive halogen species, such as hypochlorous acid, which is released by myeloperoxidase to kill pathogens. Hypochlorous acid can attack genomic DNA to produce 8-chloro-2′-deoxyguanosine (ClG) as a major lesion. It has been postulated that ClG promotes mutagenic replication using its syn conformer; yet, the structural basis for ClG-induced mutagenesis is unknown. We obtained crystal structures and kinetics data for nucleotide incorporation past a templating ClG using human DNA polymerase β (polβ) as a model enzyme for high-fidelity DNA polymerases. The structures showed that ClG formed base pairs with incoming dCTP and dGTP using its anti and syn conformers, respectively. Kinetic studies showed that polβ incorporated dGTP only 15-fold less efficiently than dCTP, suggesting that replication across ClG is promutagenic. Two hydrogen bonds between syn-ClG and anti-dGTP and a water-mediated hydrogen bond appeared to facilitate mutagenic replication opposite the major halogenated guanine lesion. These results suggest that ClG in DNA promotes G to C transversion mutations by forming Hoogsteen base pairing between syn-ClG and anti-G during DNA synthesis.
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#1Yang Yu (UCR: University of California, Riverside)H-Index: 6
#2Yuxiang Cui (UCR: University of California, Riverside)H-Index: 2
Last.Yinsheng Wang (UCR: University of California, Riverside)H-Index: 40
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#1Vinod K. Batra (NIH: National Institutes of Health)H-Index: 20
#2William A. Beard (NIH: National Institutes of Health)H-Index: 44
Last.Samuel H. Wilson (NIH: National Institutes of Health)H-Index: 76
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#1Hatem Alfakry (UH: University of Helsinki)H-Index: 5
#2Ernst Malle (Medical University of Graz)H-Index: 27
Last.Timo Sorsa (KI: Karolinska Institutet)H-Index: 78
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#1Yi Kou (University of Texas at Austin)H-Index: 5
#2Myong Chul Koag (University of Texas at Austin)H-Index: 7
Last.Seongmin LeeH-Index: 13
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#1Myong Chul Koag (University of Texas at Austin)H-Index: 7
#2Yi Kou (University of Texas at Austin)H-Index: 5
Last.Seongmin Lee (University of Texas at Austin)H-Index: 13
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