ZNF451 is an E3 SUMO-protein ligase that preferentially catalyzes SUMO2/3 conjugation over SUMO1 modification 1. The protein functions as a transcriptional coregulator, negatively regulating TGF-beta signaling through SMAD4 complex inhibition and suppressing EP300-mediated histone H3 acetylation 1. ZNF451 localizes to PML bodies and undergoes SUMOylation at multiple non-consensus sites, with SUMO modifications regulating its nuclear compartmentalization 1. In DNA damage response, ZNF451 rapidly accumulates at damage sites and catalyzes SUMO2 modification of RNF168, stabilizing this protein and enhancing histone H2A/H2AX ubiquitination for DNA double-strand break repair 2. ZNF451 collaborates with RNF8 in regulating RNF168 localization through both competitive and cooperative mechanisms 2. In cancer, ZNF451 acts as an oncogene in triple-negative breast cancer by forming complexes with SLUG transcription factor and recruiting PCAF acetyltransferase to promote CCL5 expression and tumor-associated macrophage activation 3. The protein also modulates androgen receptor target gene expression in prostate cancer cells 1. Rare ZNF451 deletions are associated with increased leukocyte telomere length, suggesting additional roles in cellular aging processes 4.