TRIM39 is an E3 ubiquitin ligase that functions as a critical regulator of cell cycle control, DNA damage responses, and inflammatory signaling. Its primary function is stabilizing p21/CDKN1A by competing with the CRL4(Cdt2) E3 ligase complex for p21 binding, thereby preventing p21 ubiquitination and degradation 1. This stabilization allows TRIM39 to regulate G1/S transition and enforce DNA damage-induced G2 arrest, with p21 serving as the crucial downstream effector 1. Beyond cell cycle control, TRIM39 negatively regulates canonical NF-κB signaling through stabilization of Cactin in an ubiquitination-independent manner 2. TRIM39 also mediates SUMOylation of ESR1, enhancing E2-ESR1 signaling 3, and promotes autophagic flux by inhibiting Rab7 ubiquitination 4. Dysregulation of TRIM39 has significant disease relevance across multiple cancer types. TRIM39 upregulation associates with poor prognosis in colorectal cancer 4 and ER+ breast cancer, where it independently predicts short disease-free survival 5. Conversely, genetic variants near TRIM39 loci provide protection against nasopharyngeal carcinoma 6, and TRIM39 upregulation mediates tumor suppressive senescence in ovarian cancer through p21 stabilization 7. TRIM39 also modulates renal fibrosis progression 8, indicating broader pathophysiological relevance beyond malignancy.