Inhibition of tryptophan 2,3-dioxygenase impairs DNA damage tolerance and repair in glioma cells
| العنوان: | Inhibition of tryptophan 2,3-dioxygenase impairs DNA damage tolerance and repair in glioma cells |
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| المؤلفون: | Maroof K. Zafar, Leena Maddukuri, Robert L. Eoff, Amit Ketkar, Stephanie D. Byrum, Alan J. Tackett, April C.L. Bostian, Megan R. Reed |
| المصدر: | Nar Cancer |
| بيانات النشر: | Cold Spring Harbor Laboratory, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | AcademicSubjects/SCI01140, 0301 basic medicine, AcademicSubjects/SCI01060, DNA damage, DNA repair, AcademicSubjects/SCI00030, SIRT7, Standard Article, AcademicSubjects/SCI01180, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Replication protein A, biology, Chemistry, General Medicine, Aryl hydrocarbon receptor, Chromatin, Cell biology, 030104 developmental biology, Histone, Sirtuin, biology.protein, Phosphorylation, AcademicSubjects/SCI00980, Signal transduction, 030217 neurology & neurosurgery, Kynurenine |
| الوصف: | Expression of tryptophan 2,3-dioxygenase (TDO) is a determinant of malignancy in gliomas through kynurenine (KYN) signaling. We report that inhibition of TDO activity attenuated recovery from replication stress and increased the genotoxic effects of bis-chloroethylnitrosourea (BCNU). Activation of the Chk1 arm of the replication stress response (RSR) was reduced when TDO activity was blocked prior to BCNU treatment, whereas phosphorylation of serine 33 (pS33) on replication protein A (RPA) was enhanced—indicative of increased fork collapse. Analysis of quantitative proteomic results revealed that TDO inhibition reduced nuclear 53BP1 and sirtuin levels. We confirmed that cells lacking TDO activity exhibited elevated gamma-H2AX signal and defective recruitment of 53BP1 to chromatin following BCNU treatment, which corresponded with delayed repair of DNA breaks. Addition of exogenous KYN increased the rate of break repair. TDO inhibition diminished SIRT7 deacetylase recruitment to chromatin, which increased histone H3K18 acetylation—a key mark involved in preventing 53BP1 recruitment to sites of DNA damage. TDO inhibition also sensitized cells to ionizing radiation (IR)-induced damage, but this effect did not involve altered 53BP1 recruitment. These experiments support a model where TDO-mediated KYN signaling helps fuel a robust response to replication stress and DNA damage. Graphical Abstract Graphical abstractThe replication stress and DNA damage responses in glioma cells are modulated by tryptophan 2,3-dioxygenase activity, a key factor controlling kynurenine signaling and de novo synthesis of NAD+. |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b3b6a536ca8038d6c8cc55a6c11f9dbcTest https://doi.org/10.1101/2020.05.28.110874Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b3b6a536ca8038d6c8cc55a6c11f9dbc |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |