Chemoresistance can result, among other, from an increased DNA repair activity. Our team is particularly interested in the human DNA glycosylase, NTH1, responsible for recognition and removal of oxidized pyrimidines from the DNA (Hans et. al., 2022), whose repair activity is stimulated by the multifunctional Y-box binding protein 1 (YB1). In the MCF7 breast tumor cell line, the YB1-NTH1 complex has been shown to lead to increased resistance to the chemotherapeutic agent, cisplatin. This prompted us to develop, a robust pipeline to rapidly screen chemical libraries and evaluate the in vivo inhibitory potential of small molecules targeting the NTH1-YB1 interface. So far six promising compounds have been identified and two of which have been shown to partially restore sensitivity of tumor cells to cisplatin (Senarisoy et. al., 2020).
Collaborations
• Philippe Frachet and Pascale Tacnet, Pixel Team, Group I2SR.
• Marie Odile Fauvarque, Emmanuelle Soleilhac, Caroline Barette, CMBA platform, CEA Grenoble.
Major publications
Hans F, Senarisoy M, Bhaskar Naidu C and Timmins J. Focus on DNA glycosylases – A set of tightly regulated enzymes with high potential as anticancer drug targets. (Review) Int. J. Mol. Sci., Special issue : Recognition of DNA lesions. (2020). 21 (23), 9226. DOI : 10.3390/ijms21239226.
Senarisoy M, Barette C, Lacroix F, De Bonis S, Stelter M, Hans F, Kleman JP, Fauvarque M-O and Timmins J. Förster resonance energy transfer-based biosensor for targeting the hNTH1-YB1 interface as a potential anti-cancer drug target. ACS Chemical Biology (2020) 15, 4, 990-1003. DOI : 10.1021/ acschembio.9b01023.
Sarre A, Stelter M, Rollo F, De Bonis S, Seck A, Hognon C, Ravanat JL, Monari A, Dehez F, Moe E and Timmins J. The three Endonuclease III variants of Deinococcus radiodurans possess distinct and complementary DNA repair activities. DNA Repair (2019) 78 p. 45-59. DOI : 10.1016/j.dnarep.2019.03.014