Interplay between DNA repair and inflammation, and the link to cancer

Abstract

DNA damage and repair are linked to cancer. DNA damage that is induced endogenously or from exogenous sources has the potential to result in mutations and genomic instability if not properly repaired, eventually leading to cancer. Inflammation is also linked to cancer. Reactive oxygen and nitrogen species (RONs) produced by inflammatory cells at sites of infection can induce DNA damage. RONs can also amplify inflammatory responses, leading to increased DNA damage. Here, we focus on the links between DNA damage, repair, and inflammation, as they relate to cancer. We examine the interplay between chronic inflammation, DNA damage and repair and review recent findings in this rapidly emerging field, including the links between DNA damage and the innate immune system, and the roles of inflammation in altering the microbiome, which subsequently leads to the induction of DNA damage in the colon. Mouse models of defective DNA repair and inflammatory control are extensively reviewed, including treatment of mouse models with pathogens, which leads to DNA damage. The roles of microRNAs in regulating inflammation and DNA repair are discussed. Importantly, DNA repair and inflammation are linked in many important ways, and in some cases balance each other to maintain homeostasis. The failure to repair DNA damage or to control inflammatory responses has the potential to lead to cancer.

Figure 1

NF-κB and the interplay between DNA repair and inflammation. NF-κB is a master regulator of the inflammatory response. After activation through TLR4, several proinflammatory genes are activated, including IL6, STAT3 and TNFα, which has the potential to lead to a cytokine storm. NF-κB is also induced by DNA damage, ROS and hypoxia, leading to the expression of proinflammtory genes. Induction of NF-κB by DNA damage is regulated by ATM, a master regulation of the DNA damage response, and this occurs with assistance from NEMO. Induction of NF-κB also leads to the induction of miR-21 and miR-210, resulting in induction of IL10, and anti-inflammatory cytokine, but also downregulation of PTEN, CDC25A and RAD52, proteins that are involved in the DNA damage response. Not only does hypoxia induce activation NF-κB, but it also induces expression of miR-155, which downregulates mismatch repair, with the potential to lead to genomic instability. However, IL10, which is indirectly induced by NF-κB, has the capacity to downregulate miR-155. Of special interest for this review is the finding that NF-κB stimulates the CtIP-BRCA1 complex, thereby promoting homology-directed repair (HDR). (see colour version of this figure at www.informahealthcare.com/bmg).

Figure 2

Interplay between microbiota, chronic inflammation and DNA damage in the gut. A. Healthy epithelia. Commensal microorganisms reside in the lumen, with very few pathogenic bacteria harboring the polyketide synthase (pks) pathogenicity island. B. Gut epithelia of an IL10-deficient mouse. The chronic inflammatory environment in the IL10-deficient mouse encourages enrichment of pathogenic E. coli that harbor the pks pathogenicity island. These pathogenic E. coli induce DNA damage in nearby epithelial cells that has the capacity to result in genomic instability and tumorigenesis. (see colour version of this figure at www.informahealthcare.com/bmg).

Figure 3

A model of the links between DNA damage and inflammation. Activation of the immune response occurs as a result of infection with pathogens, exposure to the microbiota of the gut and the secretory associated senescence phenotype (SASP). Acute inflammation can lead to chronic inflammation as described in this review, resulting in the generation of RONs and leading to DNA damage. Pathogens, genetic mutations in DNA repair genes and environment-associated expression of miRNAs can inactivate DNA repair, which results in a mutator phenotype, genomic instability and cancer. (see colour version of this figure at www.informahealthcare.com/bmg).