Impact of G-Quadruplexes and Chronic Inflammation on Genome Instability: Additive Effects during Carcinogenesis

Abstract

Genome instability is an enabling characteristic of cancer, essential for cancer cell evolution. Hotspots of genome instability, from small-scale point mutations to large-scale structural variants, are associated with sequences that potentially form non-B DNA structures. G-quadruplex (G4) forming motifs are enriched at structural variant endpoints in cancer genomes. Chronic inflammation is a physiological state underlying cancer development, and oxidative DNA damage is commonly invoked to explain how inflammation promotes genome instability. We summarize where G4s and oxidative stress overlap, with a focus on DNA replication. Guanine has low ionization potential, making G4s vulnerable to oxidative damage. Impacts to G4 structure are dependent upon lesion type, location, and G4 conformation. Occasionally, G4s pose a challenge to replicative DNA polymerases, requiring specialized DNA polymerases to maintain genome stability. Therefore, chronic inflammation creates a dual challenge for DNA polymerases to maintain genome stability: faithful G4 synthesis and bypassing unrepaired oxidative lesions. Inflammation is also accompanied by global transcriptome changes that may impact mutagenesis. Several studies suggest a regulatory role for G4s within cancer- and inflammatory-related gene promoters. We discuss the extent to which inflammation could influence gene regulation by G4s, thereby impacting genome instability, and highlight key areas for new investigation.

A microsatellite DNA-derived oligodeoxynucleotide attenuates lipopolysaccharide-induced acute lung injury in mice by inhibiting the HMGB1-TLR4-NF-κB signaling pathway

“…Compared with the non-G quadruplex ODN, G quadruplex ODN blocked more efficiently TLR7- and TLR9-mediated innate immune responses ( Römmler et al, 2013 ). This phenomenon might be related with the regulatory role of G quadruplex in inflammatory-related gene promoters ( Stein and Eckert, 2021 ). However, more is not always better; some new evidence suggested that inhibitory ODNs containing many G triplets, or quadruples were easy to form higher order structures, also called G4 stacks, which made their immunological and pharmacological behaviors unpredictable ( Lenert, 2010 ; Römmler et al, 2013 ; Zuffo et al, 2018 ).…”

An Adverse Outcome Pathway Network for Chemically Induced Oxidative Stress Leading to (Non)genotoxic Carcinogenesis

“…Besides direct induction of mutations as a result of oxidative DNA damage, oxidative stress can contribute to genome instability and epigenetic dysregulation. Repetitive sequences, which are particularly susceptible to DNA oxidation, can form secondary DNA structures upon oxidation . During DNA replication, recruitment of a special but error-prone DNA polymerase to these secondary DNA structures is needed for continuation of synthesis, ultimately contributing to genome instability .…”

“…Repetitive sequences, which are particularly susceptible to DNA oxidation, can form secondary DNA structures upon oxidation . During DNA replication, recruitment of a special but error-prone DNA polymerase to these secondary DNA structures is needed for continuation of synthesis, ultimately contributing to genome instability . Furthermore, ROS-induced expression of Bcl-2, following NRF2, , NF-κB, or STAT3/5 signaling, can inhibit DNA double-strand break (DSB) repair .…”

Role of the tumor microenvironment in the lymphatic metastasis of cervical cancer (Review)

“…Systemic inflammatory responses can aggravate malnutrition in patients. Inflammatory indicators have certain reference values in the diagnosis and prognosis of various malignant tumors, and research has confirmed that inflammation may promote tumor progression ( 97 ). Zhang et al ( 98 ) found that the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) were valuable for predicting LNM in gastric cancer.…”