Azathioprine and UVA Light Generate Mutagenic Oxidative DNA Damage

TLDR

Oxidative stress from reactive oxygen species is linked to malignancy, and chronic oxidative stress induced by clinical treatments may increase therapy‑related cancer risk. The study investigates whether azathioprine, an immunosuppressant, predisposes patients to UVA‑induced mutagenic DNA damage through 6‑thioguanine accumulation. Azathioprine causes 6‑thioguanine to accumulate in DNA, and UVA exposure generates a guanine sulfonate photoproduct that is bypassed by error‑prone Y‑family polymerases. UVA exposure generates ROS in 6‑TG‑laden DNA, producing synergistic mutagenesis, and all five patients on azathioprine exhibited UVA photosensitivity, offering a possible explanation for the high skin cancer incidence in long‑term transplant survivors.

Abstract

Oxidative stress and mutagenic DNA lesions formed by reactive oxygen species (ROS) are linked to human malignancy. Clinical treatments inducing chronic oxidative stress may therefore carry a risk of therapy-related cancer. We suggest that immunosuppression by azathioprine (Aza) may be one such treatment. Aza causes the accumulation of 6-thioguanine (6-TG) in patients' DNA. Here we demonstrate that biologically relevant doses of ultraviolet A (UVA) generate ROS in cultured cells with 6-TG-substituted DNA and that 6-TG and UVA are synergistically mutagenic. A replication-blocking DNA 6-TG photoproduct, guanine sulfonate, was bypassed by error-prone, Y-family DNA polymerases in vitro. A preliminary analysis revealed that in five of five cases, Aza treatment was associated with a selective UVA photosensitivity. These findings may partly explain the prevalence of skin cancer in long-term survivors of organ transplantation.