Decreased miR-24-3p potentiates DNA damage responses and increases susceptibility to COPD

The pathogenesis of Chronic Obstructive Pulmonary Disease (COPD) involves activation of the DNA damage response (DDR). However, biologic mechanisms that regulate the DDR and contribute to COPD progression are poorly understood. Because microRNAs are important regulators of the DDR, we hypothesized that microRNA expression changes cause pathologic DDR activation in COPD. Therefore, we evaluated microRNA expression arrays performed on lung samples from 172 subjects and identified miR-24-3p as the microRNA best correlated with radiographic emphysema (rho=-0.353, P=1.3e-04). In a mouse model of cigarette smoke induced emphysema, miR-24-3p inhibition increased emphysema severity. In human airway epithelial cells, miR-24-3p suppressed apoptosis in part via the BH3-only protein BIM, and miR-24-3p suppressed homology-directed DNA repair and the DNA repair protein BRCA1. Finally, we found BIM and BRCA1 are increased in lung samples from subjects with COPD and inversely correlate with miR-24-3p expression. We concluded that downregulation of miR-24-3p increases COPD susceptibility by potentiating the DNA damage response through BIM and BRCA1.