ATXN3L (ataxin 3 like) is a deubiquitinating enzyme belonging to the Josephin family that cleaves both Lys-48-linked and Lys-63-linked polyubiquitin chains in vitro 1. The protein functions as a deubiquitinase for transcription factor KLF5, regulating KLF5 stability by directly binding to it and decreasing its ubiquitination and degradation 2. Mechanistically, ATXN3L demonstrates significantly higher catalytic efficiency compared to its paralog ataxin-3 despite 85% sequence identity, with structural studies revealing they bind ubiquitin at different overlapping sites 1. The enzyme shows disease relevance across multiple conditions: it promotes breast cancer cell proliferation through KLF5 stabilization 2, exhibits differential expression in premature ovarian failure models 3, and shows altered expression in Alzheimer's disease and chrX Chagas disease placentas 45. Clinically, ATXN3L represents a potential therapeutic target for breast cancer and may serve as a biomarker for various conditions 2. Additionally, as a paralog of the SCA3-associated ATXN3 gene, ATXN3L is being investigated as a natural replacement gene in gene editing strategies for spinocerebellar ataxia type 3 treatment 6.