Satellite RNAs promote pancreatic oncogenic processes

Highly repetitive tandem arrays at the centromeric and pericentromeric regions in chromosomes, which were previously considered to be silent, are actively transcribed, particularly in cancer. This aberrant expression occurs even in K-ras-mutated pancreatic intraepithelial neoplasia (PanIN) tissues, which are precancerous lesions. To examine the biological roles of the satellite RNAs in the carcinogenesis steps, we construct mouse PanIN-derived cells expressing major satellite (MajSAT) RNA, which show increased frequencies of chromosomal instability and point mutations in genomic as well as mitochondrial DNA, affecting the cells transformation ability. We identify Y-box binding protein 1 (YBX1) as a protein that binds to MajSAT RNA. MajSAT RNA inhibits the nuclear translocation of YBX1 under stress conditions, which reduced its DNA damage repair function. The forced expression of YBX1 significantly decreases the aberrant phenotypes. These findings indicate that during the early stage of cancer development, satellite transcripts may act as “intrinsic mutagens” by inducing YBX-1 dysfunction, which may be crucial in oncogenic processes.