Inhibition of tryptophan 2,3-dioxygenase impairs DNA damage tolerance and repair in glioma cells

Abstract Expression of tryptophan 2,3-dioxygenase (TDO) is a determinant malignancy in gliomas through kynurenine (KYN) signaling. We report that inhibition TDO activity attenuated recovery from replication stress and increased the genotoxic effects bis-chloroethylnitrosourea (BCNU). Activation Chk1 arm response (RSR) was reduced when blocked prior to BCNU treatment, whereas phosphorylation serine 33 (pS33) on protein A (RPA) enhanced—indicative fork collapse. Analysis quantitative proteomic results revealed nuclear 53BP1 sirtuin levels. confirmed cells lacking exhibited elevated gamma-H2AX signal defective recruitment chromatin following which corresponded with delayed repair DNA breaks. Addition exogenous KYN rate break repair. diminished SIRT7 deacetylase chromatin, histone H3K18 acetylation—a key mark involved preventing sites damage. also sensitized ionizing radiation (IR)-induced damage, but this effect did not involve altered recruitment. These experiments support model where TDO-mediated signaling helps fuel robust