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

摘要

Transforming growth factor beta (TGFbeta) is multi-functional cytokine that is involved in the co-ordination and regulation of many cellular homeostatic processes. Compromised TGFbeta activity has been attributed to promotion of human cancers. Recent studies have identified a role for TGFbeta in response to radiation-induced DNA damage, suggesting a link between TGFbeta and the DNA damage response with implications for cancer development. In the present study the effects of TGFbeta on promoting the repair of bulky DNA damage, through modulation of nucleotide excision repair (NER), was investigated. We show that treatment of cells with exogenous TGFbeta leads to enhanced repair of DNA damage formed by polycyclic aromatic hydrocarbons and UV-C radiation; similarly cells with constitutively activated endogenous TGFbeta signaling show comparable responses. This effect of TGFbeta is independent of the cell cycle. The response to TGFbeta is decreased in cells that have compromised TGFbeta signaling through RNA interference of Smad4, and is decreased in NER deficient cells and cells with compromised NER through RNA interference of ERCC1. Increased interaction and nuclear localization of ERCC1/XPF and ERCC1/XPA proteins is observed after TGFbeta treatment. Our study represents the first experimental evidence of a role for TGFbeta 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.

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