Download MendeleyPromutagenicity of 8-Chloroguanine, A Major Inflammation-Induced Halogenated DNA Lesion.
Kou, Y., Koag, M.C., Lee, S.(2019) Molecules 24
- PubMed: 31569643
- DOI: https://doi.org/10.3390/molecules24193507
- Primary Citation of Related Structures:
6CRH - PubMed Abstract:
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 ¦Â (pol¦Â) 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 pol¦Â 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.
Organizational Affiliation:
The Division of Chemical Biology and Medicinal Chemistry, College of Pharmacy, The University of Texas at Austin, 2409 University Avenue, Austin, TX 78712, USA. yik109@hotmail.com.
