Nicolas Gillet

CDR - APOBEC3 mutational signature in cancer

After the spontaneous mutations linked with aging, the second most frequent type of mutations observed in cancer genomes is attributed to the APOBEC3 enzymes (Apolipoprotein B Editing Catalytic subunits 3 or A3s).

A3s are normal components of the innate immune system restricting viruses and retro-elements by cytidine deamination. The goal of this project is to understand the chain of events leading to the APOBEC3 mutational signature in cancer. We will focus on lung cancer as a large proportion of these tumors display A3-induced mutations.

There are several outstanding questions about A3 mutagenicity.

• What are the events inducing A3 expression? A3 mutagenesis in head and neck squamous cell carcinomas has been linked with HPV infection. We will test whether a lung viral infection can trigger A3-associated mutations.
• What are the pathways regulating A3 expression? Some A3 mRNAs are constitutively expressed in lung cells whereas no protein can be detected. Thus, we will investigate the post-transcriptional control of A3 transcripts.
• Are human A3s oncogenic in mouse models? We will evaluate human A3s mutagenic activity in mice. We will notably combine heterologous A3 expression with cigarette smoke exposure to test whether tobacco carcinogens can potentiate A3 mutagenesis.