Abstract
Genome damage and defective DNA repair are etiologically linked to several neurodegenerative disorders, including fused in sarcoma (FUS)-associated amyotrophic lateral sclerosis (ALS). However, the underlying mechanisms remain enigmatic, which is a roadblock for exploiting genome repair-targeted therapies. Our recent studies identified defects in DNA nick ligation and oxidative damage repair caused by mutations in the RNA/DNA-binding protein FUS in familial ALS patients. In healthy neurons, FUS protects the genome by facilitating PARP1-dependent recruitment of XRCC1/DNA Ligase IIIα (LigIII) to oxidized genome sites and activating LigIII via direct interaction. This is a critical step in the repair of oxidative genome damage, a foremost challenge for postmitotic neurons due to their high oxygen consumption. We discovered that mutant FUS significantly inhibited the recruitment of XRCC1/LigIII to DNA strand breaks, causing defects in DNA ligation during the repair of oxidative DNA damage, which contributed to neurodegeneration. While the FUS loss of function was responsible for the repair defects, increased oxidative genome damage due to mutant FUS aggregation could exacerbate the phenomenon. We highlight how these new molecular insights into previously undescribed DNA repair defect linked to FUS-associated neurodegeneration could provide an important opportunity for exploring DNA repair-based therapeutic avenues.