Genome Stability: From Molecular DNA Ambulances to Destructive RNA-DNA Marriages

Two lines of investigation will be covered in this talk. First, I will present how we used a combination of systems biology, genetic and molecular biology tools in yeast to identify the first molecular DNA ambulance. This line of work revealed a conserved role for motor proteins in the transport of damaged DNA for repair. Similar roles for motor proteins in mediating DNA repair have since been observed in mammals. Second, I will discuss how we have used a combination of yeast and human systems to uncover a role for the ATXN2 gene, which is mutated in amyotrophic lateral sclerosis (ALS) and spinocerebellar ataxia type 2 (SCA2), two highly debilitating and too often lethal neurodegenerative diseases. Our findings reveal a conserved role for ATXN2 in the suppression of genome destabilizing RNA-DNA hybrids, or R-loops. This line of work also highlights a molecular mechanism that can unify many neurodegenerative disease-linked genes pointing to important targets for therapeutic development. Overall, these two lines of work reveal exquisite and conserved mechanisms maintaining genome stability and show how such processes are compromised in various human diseases pointing to novel therapeutic avenues.