UBE2U is a ubiquitin-conjugating enzyme (E2) that catalyzes the covalent attachment of ubiquitin to target proteins, facilitating protein polyubiquitination and proteasome-mediated protein degradation. Mechanistically, UBE2U functions as part of the HULC complex and partners with the E3 ligase RNF17 to regulate chr1 responses at DNA double-strand breaks through the RIDDLE syndrome protein RNF168 1. The enzyme plays a critical role in DNA damage signaling, as demonstrated by its identification in screens for regulators of 53BP1 mobilization to ionizing radiation-induced breaks 1. Beyond DNA repair, UBE2U exhibits tissue-specific DNA methylation patterns, showing hypomethylation specifically in sperm compared to other body fluids, making it a useful forensic marker for tissue identification 2. Clinically, UBE2U variants have been associated with multi-system conditions including retinoschisis, cataracts, learning disabilities, and developmental delay in inherited retinal dystrophies 3. Additionally, genetic variants in UBE2U reached genome-wide significance in association with 2-hour postprandial insulin levels in a Chinese population GWAS 4, suggesting potential involvement in glucose metabolism and diabetes risk. These findings indicate UBE2U has diverse roles spanning DNA damage responses, metabolic regulation, and developmental processes.