Mechanism of tumorigenesis by abnormal modification and regulation of intracellular molecules

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In conversion of biological information from DNA to RNA and protein, these molecules are chemically modified and regulated in response to cellular conditions. The whole processes except for the DNA sequence itself are often called as epigenetic regulation in a broad sense, which includes cytosine methylation and chromatin, and posttranslational modification of proteins. Since gene function is controlled at the both DNA and protein levels, these mechanisms are frequently dysregulated in malignantly transformed and cancer cells. This research project has focused on the two regulatory mechanisms, (1) transcriptional regulation by DNA methylation and chromatin, and (2) protein modification and degradation, from the viewpoint of physiological and pathological roles in carcinogenesis. Methyl-CpG binding domain protein MBD1 represses transcription from tumor suppressor genes in cancer cells in DNA methylation-mediated manner. We found that MBD1 interacts with at least two histone methyltransferase complexes, Suv39h1-HP1 heterochromatic complex and MCAF1-SETDB1 euchromatic complex, for DNA methylation-based gene repression. During this study, we first identified MCAF1 and MCAF2 as a new epigenetic regulator family of proteins. Further, MBD1 interacts with methylpurine-DNA glycosylase to link DNA methylation and base excision repair in chromatin. Regarding protein modification, we reported that HECT-domain ubiquitin ligase hHYD ubiquitinates DNA topoisomerase II-binding protein for DNA damage response. It was also reported that PML-nuclear bodies are involved in serum response transcription of c-fos gene, and that serum response factor (SRF) is modulated by SUMO-1. Similarly, aryl hydrocarbon receptor nuclear transporter (ARNT), which is involved in chemical carcinogenesis and hypoxia-induced transcription, is modulated by SUMO conjugation system.