TGF beta promotes repair of bulky DNA damage through increased ERCC1/XPF and ERCC1/XPA interaction

Transforming growth factor beta (TGF beta) is multifunctional cytokine that is involved in the coordination and regulation of many cellular homeostatic processes. Compromised TGF beta activity has been attributed to promotion of human cancers. Recent studies have identified a role for TGF beta in response to radiation-induced DNA damage, suggesting a link between TGF beta and the DNA damage response with implications for cancer development. In this study, the effects of TGF beta on promoting the repair of bulky DNA damage, through modulation of nucleotide excision repair (NER), were investigated. We show that treatment of cells with exogenous TGF beta leads to enhanced repair of DNA damage formed by polycyclic aromatic hydrocarbons and ultraviolet-C radiation; similarly, cells with constitutively activated endogenous TGF beta signaling show comparable responses. This effect of TGF beta is independent of the cell cycle. The response to TGF beta is decreased in cells that have compromised TGF beta signaling through RNA interference of Smad4 and is decreased in NER-deficient cells and cells with compromised NER through RNA interference of excision repair cross-complementing group 1 (ERCC1). Increased interaction and nuclear localization of ERCC1/xeroderma pigmentosum (XP) F and ERCC1/XPA proteins is observed after TGF beta treatment. Our study represents the first experimental evidence of a role for TGF beta in the repair of bulky DNA damage resulting from promotion of the interaction and localization of repair protein complexes involved in the incision step of NER.