UBQLN4 is a proteasomal shuttle factor that regulates protein degradation through its ubiquitin-like (UBL) and ubiquitin-associated (UBA) domains, binding polyubiquitin chains and delivering substrates to the 26S proteasome 1. A key function is repressing homologous recombination (HR) repair: following ATM phosphorylation at DNA damage sites, UBQLN4 binds and removes ubiquitinated MRE11 from chr1, promoting its proteasomal degradation and redirecting double-strand break repair toward non-homologous end joining 1. UBQLN4 also stabilizes anti-apoptotic proteins BCL2A1 and BCL2L10 in response to DNA damage 2, and regulates p21 stability through interaction with E3 ligase RNF114, inducing cell cycle arrest via p53-dependent and independent mechanisms 3. Additionally, UBQLN4 facilitates nuclear-to-cytoplasmic export of ubiquitinated proteins and assists autophagy-mediated protein aggregate clearance 4. Disease relevance is substantial: UBQLN4 is genomically amplified across multiple cancer types, correlating with poor prognosis in 20 of 32 cancers 5. Overexpression promotes proliferation and invasion in lung cancer via PI3K/AKT pathway activation 6, while UBQLN4 amplification confers PARP inhibitor sensitivity through HR deficiency 15. UBQLN4 mutations associate with genome instability syndromes 1. Conversely, UBQLN4 downregulation in gastric cancer suggests context-dependent tumor suppressor roles 3.