Deciphering Regulatory Factors Governing A-to-I RNA Editing in Cancer

Abstract

Co- or post-transcriptional RNA modifications, such as RNA editing, alternative splicing and polyadenylation, generate transcriptome diversity and play important roles in human cancer initiation and progression. Here, we uncover Death-associated protein 3 (DAP3) as a novel repressor of adenosine to inosine (A-to-I) RNA editing and a strong oncogene in cancer. DAP3 represses A-to-I RNA editing via disrupting the binding of ADAR2 to its target transcripts. DAP3 suppresses PDZD7 protein recoding editing at the stop codon, which contributes to its oncogenic property. Moreover, we characterize DAP3 as a novel regulator of alternative splicing and polyadenylation in cancer cells. In addition, we explore the role of hypoxia in alternative splicing in breast cancer cells. We identify thousands of hypoxia-driven alternative splicing events, which are involved in cancer-related processes. In summary, we demonstrate that DAP3 and hypoxia play important roles in the regulation of transcriptome diversity in cancer cells.