Biology subjects

von Aesch, C.

Publications and source records attributed to von Aesch, C..

2 recordsLinked to original sources

bioRxiv2025

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

Human FAN1 is a structure-specific endonuclease critical for the repair of DNA interstrand crosslinks (ICLs) and the excision of extrahelical CAG repeats-whose pathological expansion underlies Huntingtons 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 new 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, we find that loss of USP7 accelerates CAG repeat expansion in an HD cellular model. Collectively, our findings establish USP7 as a critical regulator of FAN1 activity in the maintenance of genome stability, highlighting potential therapeutic opportunities for cancer and HD.

molecular biology↗

bioRxiv2024

The PIN1-p38-CtIP signaling axis protects stalled replication forks from deleterious degradation

Human CtIP plays a critical role in homologous recombination (HR) by promoting the resection of DNA double-strand breaks. Moreover, CtIP maintains genome stability through protecting stalled replication forks from nucleolytic degradation. However, the upstream signaling mechanisms governing the molecular switch between these two CtIP-dependent processes remain largely elusive. Here, we show that phosphorylation of CtIP by the p38 stress kinase and subsequent PIN1-mediated CtIP cis-to-trans isomerization is required for fork stabilization but dispensable for HR. We found that stalled forks are degraded in cells expressing non-phosphorylatable CtIP or lacking PIN1-p38 activity, while expression of a CtIP trans-locked mutant overcomes the requirement for PIN1-p38 in fork protection. We further reveal that Brca1-deficient mammary tumor cells that have acquired PARPi resistance regain chemosensitivity after PIN1 or p38 inhibition. Collectively, our findings identify the PIN1-p38-CtIP signaling pathway as a critical regulator of replication fork integrity.

molecular biology↗