USP22 interacts with PALB2 and promotes chemotherapy resistance via homologous recombination of DNA double strand breaks

Homologous recombination (HR) is a highly conserved pathway that can facilitate the repair of DNA double-strand breaks (DSBs). Several Deubiquitinases (DUBs) have been implicated as key players in DNA damage repair (DDR) through HR. Here we report USP22, a DUB that is highly overexpressed in multiple cancer types, is necessary for HR through a direct interaction with PALB2 through its C-terminal WD40 domain. This interaction stimulates USP22 catalytic activity in-vitro. Furthermore, we show USP22 is necessary for BRCA2, PALB2, and Rad51 recruitment to DSBs and this is in part through USP22 stabilizing BRCA2 and PALB2 levels. Taken together, our results describe a role for USP22 in DNA repair. Implications: This research provides new and exciting mechanistic insights into how USP22 overexpression promotes chemo-resistance in lung cancer. We believe this study, and others, will help aid in developing targeted drugs towards USP22 and known binding partners for lung cancer treatment.