Neuronal genome integrity and plasticity

Please note that this is an Ad Hoc seminar. This is a hybrid event - with the speaker attending in-person and viewable on Teams.

The DNA of neurons is continually damaged due to lifelong, high-level metabolic and transcriptional activity. In addition, recent studies have demonstrated extensive “programmed” DNA damage in differentiating post-mitotic neurons. Here, we identify these endogenous lesions as single strand break intermediates of thymine DNA glycosylase (TDG)-mediated removal of oxidized methylcytosines at neuronal enhancers. Interrupting active DNA demethylation using anti-neoplastic cytosine analogs triggers TDG-dependent neuronal cell death associated with massive chromosomal rearrangements of neuronal enhancers. This suggests that the well-known neurotoxic side effects of certain chemotherapies, also called “chemobrain,” could be linked to DNA repair processes intrinsic to normal neuronal differentiation. We will discuss recent studies that describe the interplay between programmed DNA damage, cell fate specification and mutagenesis in post-mitotic neurons.