MUS81 UFMylation at K400 promotes cell survival in response to camptothecin-induced replication stress

Abstract

Camptothecin (CPT) is a widely used chemotherapeutic drug that acts by trapping topoisomerase I (TOP1) on DNA during replication. UFMylation is a ubiquitin-like modification involved in various cellular processes, including DNA double-strand break repair. The role of UFMylation in regulating replication-induced DNA damage within cells, however, is unclear. Through in vivo screening, we ascertained that the structure-specific endonuclease MUS81 is UFMylated. MUS81 is responsible for the progression and restarting of replication forks in human cells. We show that CPT triggered the UFMylation of MUS81 at lysine 400, which in turn prevented its ubiquitination-mediated degradation. Additionally, re-expression of WT MUS81, but not UFMylation defective mutant MUS81(K400R), in MUS81-depleted cells rescued CPT-induced cytotoxicity. Thus, the study revealed a new role for UFMylation in CPT-induced DNA damage, in which MUS81 UFMylation at K400 promotes cancer cell survival by inhibiting MUS81 degradation in response to CPT treatment, thus providing an attractive therapeutic strategy combining UFMylation inhibitors with CPT.

Keywords

UFMylation / MUS81 / CPT / Ubiquitination / Cancer therapy

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Funding

National Natural Science Foundation of China(32090031)