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A Cell-Intrinsic Interferon-like Response Links Replication Stress to Cellular Aging Caused by Progerin

2018; Cell Press; Volume: 22; Issue: 8 Linguagem: Inglês

10.1016/j.celrep.2018.01.090

2639-1856

Ray Kreienkamp, Simona Graziano, Núria Coll-Bonfill, Gonzalo Bedia‐Diaz, Emily Cybulla, Alessandro Vindigni, Dale Dorsett, Nard Kubben, Luis Francisco Zirnberger Batista, Susana Gonzalo,

DNA Repair Mechanisms

Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disease caused by a truncated lamin A protein (progerin) that drives cellular and organismal decline. HGPS patient-derived fibroblasts accumulate genomic instability, but its underlying mechanisms and contribution to disease remain poorly understood. Here, we show that progerin-induced replication stress (RS) drives genomic instability by eliciting replication fork (RF) stalling and nuclease-mediated degradation. Rampant RS is accompanied by upregulation of the cGAS/STING cytosolic DNA sensing pathway and activation of a robust STAT1-regulated interferon (IFN)-like response. Reducing RS and the IFN-like response, especially with calcitriol, improves the fitness of progeria cells and increases the efficiency of cellular reprogramming. Importantly, other compounds that improve HGPS phenotypes reduce RS and the IFN-like response. Our study reveals mechanisms underlying progerin toxicity, including RS-induced genomic instability and activation of IFN-like responses, and their relevance for cellular decline in HGPS.