Paper

NLRP3 controls ATM activation in response to DNA damage

Bodnar-Wachtel, Mélanie, Py, Bénédicte, Ghiringhelli, Francois, Hall, Janet, Goutagny, Nadège, Bartosch, Birke, Couté, Yohann, Huber, Anne-Laure, Baptiste Guey, Lantuejoul, Sylvie, Ballot, Elise, Gerossier, Laetitia, Hacot, Sabine, Gorry, Julie, Ballesta, Annabelle, Petrilli, Virginie

2020

Overview

The DNA damage response (DDR) is essential to preserve genomic integrity and acts as a barrier to cancer. The ATM pathway orchestrates the cellular response to DNA double strand breaks (DSBs), and its attenuation is frequent during tumorigenesis. Here, we show that NLRP3, a Pattern Recognition Receptor known for its role in the inflammasome complex formation, interacts with the ATM kinase to control the early phase of DDR, independently of its inflammasome activity. NLRP3 down-regulation in human bronchial epithelial cells impairs ATM pathway activation as shown by an altered ATM substrate phosphorylation profile, and due to impaired p53 activation, confers resistance to acute genomic stress. Moreover, we found that NLRP3 is down-regulated in Non-Small Cell Lung Cancer (NSCLC) tissues and NLRP3 expression is correlated with patient overall survival. NLRP3 re-expression in NSCLC cells restores appropriate ATM signaling. Our findings identify a non-immune function for NLRP3 in genome integrity surveillance and strengthen the concept of a functional link between innate immunity and DNA damage sensing pathways. Competing Interest Statement The authors have declared no competing interest.

• Publisher: Cold Spring Harbor Laboratory Press,Cold Spring Harbor Laboratory
• Subject: Cancer Biology / Cell activation / Deoxyribonucleic acid / DNA / DNA damage / Down-regulation / Epithelial cells / Genomes / Genomics / Immune response / Inflammasomes / Innate immunity / Non-small cell lung carcinoma / p53 Protein / Pattern recognition receptors / Phosphorylation / Small cell lung carcinoma / Tumorigenesis