KAISO, a critical regulator of p53-mediated transcription of CDKN1A and apoptotic genes

• Published in: Proceedings of the National Academy of Sciences - PNAS 2014-10, Vol.111 (42), p.15078-15083
• Main Authors: Koh, Dong-In, Han, Dohyun, Ryu, Hoon, Choi, Won-Il, Jeon, Bu-Nam, Kim, Min-Kyeong, Kim, Youngsoo, Kim, Jin Young, Parry, Lee, Clarke, Alan R., Reynolds, Albert B., Hur, Man-Wook
• Format: Article
• Language: English
• Subjects: Acetylation; Animals; Apoptosis; Binding sites; Biological Sciences; Cell Cycle; Cell cycle proteins; Cell Line; Cell Proliferation; Cells; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; DNA; DNA - chemistry; DNA Damage; DNA Methylation; E1A-Associated p300 Protein - metabolism; Female; Fibroblasts - cytology; Genes; HCT116 Cells; HEK293 Cells; Humans; Mice; Mice, Inbred C57BL; Mice, Knockout; Promoter Regions, Genetic; Protein Binding; Proteins; Response Elements; Transcription Factors - metabolism; Transcriptional regulatory elements; Tumor Suppressor Protein p53 - metabolism; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1318780111

Significance Transcription factor KAISO (POZ/BTB family protein, ZBTB33) expression is induced by genotoxic stress in a tumor suppressor p53-dependent manner. KAISO then interacts with p53 and the acetyltransferase p300 to modulate p300 acetylation of p53 and imposing upon p53 a “code,” i.e., acetylation at K320 and K382, and inhibition of acetylation at K381. This coded p53 shows increased DNA binding to p53 response elements in the promoters of CDKN1A (cyclin-dependent kinase inhibitor 1) and apoptosis genes, subsequently inducing cell cycle arrest and potent apoptosis. KAISO is a critical regulator of DNA damage responses in multiple cell types and carries out this function by regulating p53-mediated cell cycle arrest and apoptosis. An unresolved issue in genotoxic stress response is identification of induced regulatory proteins and how these activate tumor suppressor p53 to determine appropriate cell responses. Transcription factor KAISO was previously described to repress transcription following binding to methylated DNA. In this study, we show that KAISO is induced by DNA damage in p53-expressing cells and then interacts with the p53–p300 complex to increase acetylation of p53 K320 and K382 residues, although decreasing K381 acetylation. Moreover, the p53 with this particular acetylation pattern shows increased DNA binding and potently induces cell cycle arrest and apoptosis by activating transcription of CDKN1A (cyclin-dependent kinase inhibitor 1) and various apoptotic genes. Analogously, in Kaiso KO mouse embryonic fibroblast cells, p53-to-promoter binding and up-regulation of p21 and apoptosis gene expression is significantly compromised. KAISO may therefore be a critical regulator of p53-mediated cell cycle arrest and apoptosis in response to various genotoxic stresses in mammalian cells.