The DNA-repair protein APE1 contributes with hnRNPA2B1 to motif-enriched miRNA secretion

The base excision repair (BER) Apurinic/apyrimidinic endonuclease 1 (APE1) enzyme is endowed with several non-repair activities, such as the cell response to genotoxic stress, the regulation of gene expression and miRNAs processing. We recently demonstrated that APE1 can be actively secreted by mammalian cells through exosomes. The role of APE1 in exosomes is still unknown, especially regarding the molecular mechanism involving small non-coding RNAs vesicular secretion. miRNAs loading into exosomes is a regulated and selective process, since not all the expressed miRNAs are indistinctly conveyed into exosomes. Through a dedicated transcriptomic analysis on cellular and vesicular small RNAs, we identified secreted miRNAs characterized by enriched sequence motifs and possible binding sites for APE1. In 50 out of 53 DE-miRNA precursors, we surprisingly found EXO motifs and proved that APE1 cooperates with hnRNPA2B1 for the EV-sorting of a subsets of miRNAs, including miR-1246, through a direct binding to GGAG stretch. We provide evidence of a new post-transcriptional role for this ubiquitous DNA-repair enzyme towards miRNAs secretion mechanisms, that could be exploited to interfere with tumor microenvironment.