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

Activation of the DNA damage response (DDR) due to chronic exposure to cigarette smoke (CS) is implicated in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). However, not all smokers develop COPD and the pathologic consequences of CS exposure are heterogenous. Cellular mechanisms that regulate the DDR and contribute to disease progression in susceptible individuals are poorly understood. Because microRNAs are well known regulators of the DDR, we evaluated microRNA expression arrays performed on lung samples from 172 subjects with and without COPD. We identified miR-24-3p as the microRNA best correlated with radiographic emphysema (ρ=-0.353, P=1.3e-04) and validated this finding in multiple cohorts. In a CS-exposure mouse model, miR-24-3p inhibition increased emphysema severity. In human airway epithelial cells, miR-24-3p suppressed apoptosis through the BH3-only protein BIM and suppressed homology-directed DNA repair and the DNA repair protein BRCA1. Finally, we found BIM and BRCA1 were increased in COPD lung tissue and inversely correlated with miR-24-3p expression. We concluded that decreased miR-24-3p expression increases COPD susceptibility and potentiates the DDR through BIM and BRCA1. ### Competing Interest Statement EF is currently employed by Rubius Therapeutics; VN is currently employed by Akoya Bioscience; RB is cofounder and consultant for Cybrexa Therapeutics; MS and PJL are co-inventors on a pending patent describing the therapeutic utility of MIF020 in lung disease; NK reports personal fees from Biogen Idec, Boehringer Ingelheim, Third Rock, Miragen, Pliant, Samumed, NuMedii, Indaloo, Theravance, LifeMax, Optikira, Three Lake Partners and has filed patents related to the use of thyroid hormone as an antifibrotic agent and novel biomarkers in pulmonary fibrosis.