Fig. 1. The mechanistic components behind a mutagenic process.

Almost all mutations can be traced back to a sequence of events in which first, the DNA is chemically altered by reactive species generating a DNA lesion (L1, L2, L3, etc.; left panel). Several sources of reactive species are depicted: exogenous chemicals, such as aflatoxin B1 and inflammatory mediators (paths 1a and 3); inflammation and associated processes that generate endogenous reactive species (reactive oxygen, nitrogen and halogen species; path 1b), as well as secondary reactive products (path 2; lipid oxidation-derived aldehydes); endogenous enzymes that directly modify DNA bases (APOBEC family deaminases). One additional pathway that leads to DNA lesions is the incorporation of a damaged nucleotide, generated by some of the same reactive species above (path 4). Most lesions are typically detected and repaired by the DNA repair pathways, before they get a chance to be replicated (middle panel). Finally, during replication, the DNA lesion may miscode, leading to a mismatch. In a subsequent replication, or during an attempt at mismatch repair, this mismatch will lead to a point mutation (right panel).