Emerging Roles of Non-canonical RNA Binding Proteins in the Repair of Genome Damage Linked to Human Pathologies

Genome maintenance and repair in higher organisms are complex and orchestrated by both canonical and non-canonical factors. The involvement of RNA binding proteins, including members of the heterogeneous nuclear ribonucleoprotein family, has been recently discovered in DNA repair. We and others documented stimulatory function of heterogeneous nuclear ribonucleoprotein-U in the repair of oxidized DNA bases. Subsequent studies established direct involvement of several RNA binding proteins in genome repair in various cell types, including postmitotic neurons. While etiologic involvement of genome damage in cancer initiation and progression is well established, multiple studies link deficiency in repair of neuronal genome damage to neurodegenerative diseases. Such repair defects are often associated with toxic mutations in one or more RNA binding proteins. Our recent studies delineated specific mechanisms of TAR DNA binding protein, TDP-43 and fused in sarcoma, FUS, in DNA strand-break repair. TDP-43 participates in non-homologous end joining-mediated DNA double-strand break repair, whereas FUS activates DNA ligase 3 in base excision and DNA single-strand break repair. These studies uncovering the non-canonical role of RNA binding proteins in genome repair not only underscore their multi-tasking functions in RNA and DNA transactions but also highlight their participation in promoting repair in preventing diverse human pathologies.