Abstract PR01: Structural mechanism of sequence-specific 5-methylcytosine (5mC) recognition by AP-1 transcription factors

Abstract

Abstract DNA methylation is generally known to inhibit transcription factor binding. However, this notion has been challenged with identifications of several transcription factors that preferentially activate methylated promoters in specific sequences. AP-1 transcription factor (c-Jun/c-Fos heterodimer), a master regulator of a wide range of cancer-related genes, has been shown to bind a novel consensus sequence (5'-TGACTCG-3') in CpG methylation-dependent manner. In the fluorescence polarization-based DNA binding assay, both c-Jun/c-Fos heterodimer and c-Jun/c-Jun homodimer preferentially bind DNA containing the methylated consensus sequence compared to DNA with unmethylated sequence. Using a homodimer of c-Jun/c-Jun basic leucine zipper (bZIP) DNA binding domain, we have solved the X-ray structure of AP-1 in complex with an oligonucleotide containing the methylated consensus sequence. The structure reveals that a common motif conserved among bZIP proteins is involved in the specific recognition of methylated CpG by one monomer and TpG by the other monomer. Like 5mC, thymine (5-methyluracil) contains a methyl group at C5 position, and the similarity imposed by the methyl C5 preserves key structural features of DNA sequence recognized by AP-1. Our in vitro finding resonates with previous studies of AP-1-like transcription factors that preferentially bind methylated response elements. In light of such evidence, our characterization of AP-1 as a sequence-specific 5mCpG and TpG reader suggests a novel way in which DNA methylation may function to activate transcription in a methylation-dependent manner. Citation Format: Samuel Hong, Xiaodong Cheng. Structural mechanism of sequence-specific 5-methylcytosine (5mC) recognition by AP-1 transcription factors. [abstract]. In: Proceedings of the AACR Special Conference on Chromatin and Epigenetics in Cancer; Sep 24-27, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2016;76(2 Suppl):Abstract nr PR01.