CUL9 (cullin 9) functions as a core component of a Cul9-RING ubiquitin-protein ligase complex with RBX1, forming a unique 1.8-MDa hexameric assembly that encompasses both cullin-RING and RBR domains 1. The CUL9-RBX1 complex mediates ubiquitination and degradation of key substrates including BIRC5 (survivin), which is essential for maintaining microtubule dynamics and genome integrity 2. CUL9 also mono-ubiquitinates p53/TP53 and acts as its cytoplasmic anchor protein, regulating p53 subcellular localization and function 1. This regulation is critical for p53-dependent cellular responses, as CUL9 deletion attenuates DNA damage-induced apoptosis and p21 induction 34. The complex utilizes E2 ubiquitin-conjugating enzymes UBE2L3 and UBE2D2 for its ubiquitination activity 1. CUL9 functions downstream of the 3M complex in a pathway that maintains microtubule and genome integrity 2. Functionally, CUL9 serves as a tumor suppressor, as Cul9-null mice develop spontaneous tumors, exhibit increased DNA damage and aneuploidy 32. The tumor suppressive function is largely p53-dependent, with CUL9-p53 interactions being essential for proper cellular responses to DNA damage and maintenance of genome stability 4.