Abstract
Highly repetitive tandem arrays at the centromeric and pericentromeric regions in chromosomes, previously considered 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 carcinogenesis, we construct mouse PanIN-derived cells expressing major satellite (MajSAT) RNA and show increased malignant properties. We find an increase in frequency of chromosomal instability and point mutations in both genomic and mitochondrial DNA. 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, thus reducing 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 YBX1 dysfunction, which may be crucial in oncogenic processes.
Highlights
Repetitive tandem arrays at the centromeric and pericentromeric regions in chromosomes, previously considered silent, are actively transcribed, in cancer
With the previous report[18], major satellite (MajSAT) RNA was expressed in cancer cells as well as in pancreatic intraepithelial neoplasia (PanIN) cells, while no MajSAT RNA expression was observed in wildtype tissues (Fig. 1a)
Because the transcript lengths of MajSAT RNA were highly heterogeneous, they were detected as smear or ladder bands covering from B200 to 8,000 nucleotide, which was consistent with other reports[18,26] (Fig. 1b)
Summary
Repetitive tandem arrays at the centromeric and pericentromeric regions in chromosomes, previously considered silent, are actively transcribed, in cancer This aberrant expression occurs even in K-ras-mutated pancreatic intraepithelial neoplasia (PanIN) tissues, which are precancerous lesions. Some reports have shown that the appropriate transcription of these satellite regions is essential for accurate cell division[12,13,14], heterochromatin establishment in mouse embryonic development[15,16] and cell differentiation[17] In contrast to these physiological roles, the aberrant transcription of satellite sequences can be observed in epithelial tumours, especially in pancreatic cancers including PanIN lesions[18]. We show that aberrantly expressed MajSAT RNA in PanIN-derived cells increases the chromosomal instability and mutations in genomic and mitochondrial DNAs (mtDNA), by inducing YBX1 dysfunction. The increased instability and mutations due to satellite RNAs may molecularly explain the process of the transformation of precancerous cells to invasive cancers
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