DNA Repair, ADP-Ribosylation, and Cancer

The team's research aims to elucidate the mechanisms involved in DNA damage signaling, ADP-ribosylation, and DNA repair in response to genotoxic stress, in order to better understand how resistance to treatment develops in tumor cells, particularly in kidney cancer.

• Research Area 1: Characterization of DNA ADP-ribosylation by PARPs and its role in DNA break repair.

• Research Area 2: Study of DNA damage signaling pathways in kidney cancer, particularly in its hereditary forms.

• Research Area 3: Investigation of the role of thymine-DNA glycosylase (TDG) and epigenetic modifications (5hmC) in tumor adaptation.

Our research shows that PARP1-3 can directly modify DNA ends and that this modification is reversible, suggesting a dynamic mechanism coordinating the repair of complex damage. We are analyzing its mechanisms, regulation, and contribution to resistance to chemotherapy.

We have identified and characterized new genes associated with a predisposition to renal cell carcinoma (RCC), notably Apollo, which is involved in telomere protection. We are currently developing new cellular models with different genotypes of a gene of interest (VHL) and patient samples (tumoroids), which will enable us to identify molecular alterations involved in tumorigenesis and response to treatment.

We have also shown that TDG catalyzes the excision of T, C, and 5hmC residues in double-stranded DNA, which can lead to the formation of persistent single-strand breaks in unmethylated or hydroxymethylated chromatin regions.

The insights gained from these mechanistic studies should lead to the identification of new diagnostic markers and therapeutic targets.