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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE230874 | GEO | 2024/07/24

REPOSITORIES: GEO

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Project description:The presence of oxidized DNA lesions, such as 7,8-dihydro-8-oxoguanine (8-oxoG) and apurinic/apyrimidinic sites (AP sites), has been described as epigenetic signals that are involved in gene expression control. In mammals, Apurinic-apyrimidinic endonuclease 1/Redox factor-1 (APE1/Ref-1) is the main AP endonuclease of the base excision repair (BER) pathway and is involved in active demethylation processes. In addition, APE1/Ref-1, through its redox function, regulates several transcriptional factors. However, the transcriptional control targets of each APE1 function are not completely known. In this study, a transcriptomic approach was used to investigate the effects of chemical inhibition of APE1/Ref-1 redox or DNA repair functions by E3330 or methoxyamine (MX) in an inflammatory cellular model. Under lipopolysaccharide (LPS) stimulation, both E3330 and MX reduced the expression of some cytokines and chemokines. Interestingly, E3330 treatment reduced cell viability after 48 h of the treatment. Genes related to inflammatory response and mitochondrial processes were downregulated in both treatments. In the E3330 treatment, RNA processing and ribosome biogenesis genes were downregulated, while they were upregulated in the MX treatment. Furthermore, in the E3330 treatment, the cellular stress response was the main upregulated process, while the cellular macromolecule metabolic process was observed in MX-upregulated genes. Nuclear respiratory factor 1 (NRF1) was predicted to be a master regulator of the downregulated genes in both treatments, while the ETS transcription factor ELK1 (ELK1) was predicted to be a master regulator only for E3330 treatment. Decreased expression of ELK1 and its target genes and a reduced 28S/18S ratio were observed, suggesting impaired rRNA processing. In addition, both redox and repair functions can affect the expression of NRF1 and GABPA target genes. The master regulators predicted for upregulated genes were YY1 and FLI1 for the E3330 and MX treatments, respectively. In summary, the chemical inhibition of APE1/Ref-1 affects gene expression regulated mainly by transcriptional factors of the ETS family, showing partial overlap of APE1 redox and DNA repair functions, suggesting that these activities are not entirely independent. This work provides a new perspective on the interaction between APE1 redox and DNA repair activity in inflammatory response modulation and transcription.

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

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