USP7 deubiquitinase stabilizes FAN1 to support DNA crosslink repair and suppress CAG repeat expansion

Abstract

Human FAN1 is a structure-specific endonuclease implicated in the repair of DNA interstrand crosslinks (ICLs) and the excision of extrahelical CAG repeats–whose pathological expansion underlies Huntington’s disease (HD), a progressive and currently incurable neurodegenerative disorder. However, mechanisms of post-translational regulation of FAN1 are still largely unknown. Here, we identify the ubiquitin-specific protease 7 (USP7) as an interactor of FAN1. USP7 stabilizes FAN1 protein levels in a deubiquitination-dependent manner, preventing FAN1 from proteasomal degradation. Consequently, we demonstrate that USP7 depletion leads to reduced chromatin association of FAN1 and increased cellular hypersensitivity following ICL damage. Moreover, loss of USP7 accelerates CAG repeat expansion in an RPE-1 cell model stably expressing mutant huntingtin (mHTT) exon 1 containing 129 CAG repeats (RPE-1HTT-CAG129). Collectively, our findings uncover a link between USP7 and FAN1 in mechanisms that preserve genome stability and influence repeat instability.