UCHL3 Regulates Topoisomerase-Induced Chromosomal Break Repair by Controlling TDP1 Proteostasis

摘要

Genomic damage can feature DNA-protein crosslinkswhereby their acute accumulation is utilized totreat cancer and progressive accumulation causesneurodegeneration. This is typified by tyrosyl DNAphosphodiesterase 1 (TDP1), which repairs topoisomerase-mediated chromosomal breaks. AlthoughTDP1 levels vary in multiple clinical settings, themechanism underpinning this variation is unknown.We reveal that TDP1 is controlled by ubiquitylationand identify UCHL3 as the deubiquitylase that controlsTDP1 proteostasis. Depletion of UCHL3 increasesTDP1 ubiquitylation and turnover rate andsensitizes cells to TOP1 poisons. Overexpression ofUCHL3, but not a catalytically inactive mutant,suppresses TDP1 ubiquitylation and turnover rate.TDP1 overexpression in the topoisomerase therapy-resistant rhabdomyosarcoma is driven byUCHL3 overexpression. In contrast, UCHL3 is downregulatedin spinocerebellar ataxia with axonal neuropathy(SCAN1), causing elevated levels of TDP1ubiquitylation and faster turnover rate. These dataestablish UCHL3 as a regulator of TDP1 proteostasisand, consequently, a fine-tuner of protein-linkedDNA break repair.