KLHL15 encodes a substrate-specific adapter protein that functions within CUL3-based E3 ubiquitin ligase complexes to regulate protein degradation 1. The protein contains an N-terminal BTB/POZ domain and C-terminal kelch motifs, which are conserved across vertebrate species 2. KLHL15 targets multiple substrates for ubiquitination and proteasomal degradation through recognition of specific sequence motifs. Key substrates include the DNA repair protein CtIP/RBBP8, which contains a conserved FRY tripeptide motif essential for KLHL15 binding 1. By degrading CtIP, KLHL15 inhibits DNA-end resection and promotes error-prone non-homologous end joining over homologous recombination repair 1. KLHL15 also targets doublecortin (DCX) family proteins through similar FRY motifs, regulating neuronal dendrite development 3. Additionally, it promotes degradation of the PP2A regulatory subunit PPP2R5B/B'β, facilitating exchange with other regulatory subunits and controlling phosphatase activity 4. Disease relevance includes X-linked intellectual disability, with pathogenic variants identified in affected families 56. The protein shows ubiquitous tissue expression and plays critical roles in DNA damage response, neuronal development, and cellular signaling through its regulation of protein stability 23.