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

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 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.

Transcriptomic profile of the mice aging lung is associated with inflammation and apoptosis as important pathways

“…These findings support the notion that inflammaging, the chronic, low-grade inflammation that develops with age, is a common process of normal lung aging and may contribute to susceptibility to age-related pathologies [ 24 ], including DNA lesion-induced carcinogenesis [ 25 ]. Actually, a recent published systematic review and meta-analysis provides epidemiological data on the relationship between chronic inflammation and cancer incidence including lung cancer [ 26 ].…”

Cause of death among patients with colorectal cancer: a population-based study in the United States

“…Systematic therapy for metastatic CRC is tailored with disease-specific and patient-specific predictive markers. With the progress in the research of tumorigenic mechanism, many potential therapy targets have been found [ 22 – 24 ], which contributed greatly to the prognosis of CRC patients. Paralleled with the breakthroughs in surgical and allied areas, the increasing kinds and number of effective drugs for CRC has led to considerable improvements of overall survival.…”

Identification and validation of the angiogenic genes for constructing diagnostic, prognostic, and recurrence models for hepatocellular carcinoma

“…Given the complexity of the mechanism of tumor carcinogenesis, fighting cancer has been a long and arduous task for many years [45][46][47]. In the field of anticancer, especially for HCC and other types of cancers that are prone to appear due to changes in various chemical substances, inflammations and molecular markers, the carcinogenic mechanism and corresponding drug development have made gratifying progress [48][49][50]. In this study, we also aimed to explore the practical value of these angiogenic genes in clinically targeted therapy, we found through pharmacological analysis that piperlongumine was an inhibitor of EGF/EGFR.…”