RNF138 is an E3 ubiquitin ligase that plays critical roles in DNA damage response and cellular signaling pathways. The protein primarily functions in DNA double-strand break repair by promoting homologous recombination through two proposed mechanisms: ubiquitinating XRCC5/Ku80 to remove the Ku complex from DNA breaks, or cooperating with UBE2D ligases to ubiquitinate RBBP8/CtIP 12. RNF138 is recruited to sites of double-strand breaks and is essential for DNA end resection, with its activity regulated by CDK phosphorylation at T27 and ubiquitylation at K158 during S/G2 phases 3. Beyond DNA repair, RNF138 exhibits diverse cellular functions including regulation of the Wnt/β-catenin pathway by stabilizing β-catenin through APC degradation, promoting skeletal muscle differentiation 4. The protein also acts as a tumor suppressor by inhibiting NF-κB signaling through preventing NIBP translocation, with RNF138 deficiency leading to increased susceptibility to colorectal cancer 5. Additionally, RNF138 regulates inflammatory responses by degrading SMARCC1 of the SWI/SNF complex 6 and controls myeloid differentiation by targeting C/EBPα for proteasomal degradation 7. These multifaceted roles highlight RNF138 as a crucial regulatory protein in genomic stability and cellular homeostasis.