Two ZNF509 (ZBTB49) isoforms induce cell-cycle arrest by activating transcription of p21/CDKN1A and RB upon exposure to genotoxic stress

• Published in: Nucleic acids research 2014-10, Vol.42 (18), p.11447-11461
• Main Authors: Jeon, Bu-Nam, Kim, Min-Kyeong, Yoon, Jae-Hyeon, Kim, Min-Young, An, Haemin, Noh, Hee-Jin, Choi, Won-Il, Koh, Dong-In, Hur, Man-Wook
• Format: Article
• Language: English
• Subjects: Cell Cycle Checkpoints; Cell Line; Cell Proliferation; Cyclin-Dependent Kinase Inhibitor p21 - biosynthesis; Cyclin-Dependent Kinase Inhibitor p21 - genetics; DNA Damage; DNA-Binding Proteins - biosynthesis; DNA-Binding Proteins - chemistry; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene regulation, Chromatin and Epigenetics; HEK293 Cells; Humans; Kruppel-Like Transcription Factors - metabolism; Neoplasms - metabolism; p300-CBP Transcription Factors - metabolism; Promoter Regions, Genetic; Protein Isoforms - biosynthesis; Protein Isoforms - chemistry; Protein Isoforms - genetics; Protein Isoforms - metabolism; Retinoblastoma Protein - biosynthesis; Retinoblastoma Protein - genetics; Stress, Physiological - genetics; Transcription Factors - biosynthesis; Transcription Factors - chemistry; Transcription Factors - genetics; Transcription Factors - metabolism; Transcriptional Activation; Tumor Suppressor Protein p53 - metabolism; Zinc Fingers
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gku857

ZNF509 is unique among POK family proteins in that four isoforms are generated by alternative splicing. Short ZNF509 (ZNF509S1, -S2 and -S3) isoforms contain one or two out of the seven zinc-fingers contained in long ZNF509 (ZNF509L). Here, we investigated the functions of ZNF509 isoforms in response to DNA damage, showing isoforms to be induced by p53. Intriguingly, to inhibit proliferation of HCT116 and HEK293 cells, we found that ZNF509L activates p21/CDKN1A transcription, while ZNF509S1 induces RB. ZNF509L binds to the p21/CDKN1A promoter either alone or by interacting with MIZ-1 to recruit the co-activator p300 to activate p21/CDKN1A transcription. In contrast, ZNF509S1 binds to the distal RB promoter to interact and interfere with the MIZF repressor, resulting in derepression and transcription of RB. Immunohistochemical analysis revealed that ZNF509 is highly expressed in normal epithelial cells, but was completely repressed in tumor tissues of the colon, lung and skin, indicating a possible role as a tumor suppressor.