The DNA of cancer cells is often damaged and altered by mutations. These alterations can occur spontaneously, but can also be induced by certain cancer treatments. The ability of these tumour cells to detect and repair this damage is a major determinant of their survival in the presence of cancer treatments and often involves the hyperactivation of DNA repair factors.
Understanding the mechanisms of DNA repair within our cells is therefore essential for identifying new molecular targets that could form the basis of new therapeutic strategies.
Understanding the mechanisms of DNA repair within our cells is therefore essential for identifying new molecular targets that could form the basis of new therapeutic strategies.
The team is particularly interested in understanding the factors that regulate the Base Excision Repair (BER) pathway in the context of cancer. The BER pathway is responsible for the elimination of small, non-helix distorting, base lesions, including oxidized bases resulting from exposure to ionizing radiation or oxidative stress.
Current projects in the team related to this topic include the characterization of the interactions of two multifunctional cellular stress response factors, the Y-Box binding protein 1 (YB1) and nucleophosmin 1 (NPM1), with two key BER factors, the DNA glycosylase NTH1 and the AP endonuclease APE1.
YB1 is a human stress response factor that directly interacts with the DNA glycosylase NTH1, enhancing its capacity to recognize and excise oxidized pyrimidines. By stimulating this repair activity, YB1 contributes to genome stability under oxidative stress but also promotes the emergence of chemoresistant cancer cells. The team has identified several small-molecule inhibitors targeting the NTH1–YB1 complex that partially restore cisplatin sensitivity in breast cancer cells (Senarisoy et al., 2020). More recent studies further highlight YB1’s strong potential as a pan-cancer biomarker, underscoring its relevance as both a therapeutic target and a diagnostic and prognostic marker.
NPM1 is a human protein involved in several biological processes, which has been identified as a key player in several DNA repair pathways, including the BER pathway. NPM1 influences the stability, activity, and nucleolar localization of several BER factors, including APE1. APE1 is an enzyme that recognizes and modifies abasic (AP) sites to allow DNA polymerase to fill in the missing nucleotide(s). Although the interaction between NPM1 and APE1 is crucial for maintaining the efficiency of DNA repair, it appears to be deleterious in many cancers, where the cooperation of the two proteins is involved in the resistance of tumour cells to commonly used chemotherapies.
Collaborations
• Marie Odile Fauvarque, Emmanuelle Soleilhac, Caroline Barette, CMBA platform, CEA Grenoble.
• Fabienne Meggetto, CRCT, Toulouse.
• Malene Jensen (SIGNAL group, IBS)
• Guy Schoehn (MEM group, IBS)
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