Medical Scientist-Programm 2020

Thema: "Repurposing of atypical cell cycle activity in differentiated neurons for alternative DNA repair under CNS aging and neurodegeneration"

Zusammenfassung:
Still unresolved is the question of how differentiated neurons maintain genomic integrity over lifetime in spite of their exposure to high metabolically-induced oxidative stress levels, their non-replaced nature and the incompetence to utilize error-free homologous recombination for DNA double strand break repair. In continuation of our recent work, we address that differentiated neurons preserve a functional cell cycle machinery and activate atypical cell cycle events under stress conditions, as evidenced for CNS aging and neurodegeneration, in the context of DNA repair. In compliance to our observations that predominantly G1 phase is recapitulated, we introduce a model in which increased cyclin D1 levels of re-activated G1 facilitate a cyclin D1-RAD51/52-dependent DNA repair mechanism that is independent of sister chromatid templates, however, requires active transcription. Thus, atypical cell cycle might be repurposed with ambivalent functions, by inducing apoptosis at instance of fatal DNA damage, but rescuing the neuron in case of repairable genomic injury. Further studies will elucidate how far this mechanism can substitute for homologous recombination-mediated repair. In summary, we assume a yet unappreciated role of unscheduled cell cycle re-induction in DNA repair choice decisions that will assist neurons to preserve DNA integrity under genomic stress.