Revisiting the action spectrum of DNA damage: Chemiexcitation and the expanded biological spectrum of cyclobutane pyrimidine dimer formation.

The action spectrum of cyclobutane pyrimidine dimer (CPD) formation has long been viewed as reflecting the DNA absorption spectrum and closely aligned with the erythema (sunburn) spectrum. This alignment established the prevailing paradigm in which erythema serves as a surrogate for mutagenic risk and ultraviolet B radiation (UVB) is responsible for biologically meaningful DNA damage in skin. However, the discovery of delayed or "dark" CPDs, generated through post-exposure biochemical processes such as melanin-dependent chemiexcitation, extends and refines this classical view. It is increasingly well established that CPD formation is not limited to direct photon absorption but can additionally arise through longer-wavelength, redox-driven chemiexcitation pathways, particularly within the UVA range. Emerging evidence further suggests that non-melanin oxidative pathways, including lipid peroxidation, can generate chemiexcited states potentially relevant to DNA damage. In light of this evidence, we propose that the biological action spectrum for CPD formation is determined not only by direct DNA absorption, but also by the capacity of cells to generate DNA damaging excited states through redox chemistry. This novel framework reshapes how light exposure is linked to mutagenesis and underscores the need for next-generation photoprotective strategies targeting both direct and indirect DNA damage pathways.