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

• Main Authors: Ray Kreienkamp, Simona Graziano, Nuria Coll-Bonfill, Gonzalo Bedia-Diaz, Emily Cybulla, Alessandro Vindigni, Dale Dorsett, Nard Kubben, Luis Francisco Zirnberger Batista, Susana Gonzalo
• Format: Article
• Language: English
• Published: Elsevier 2018-02-01
• Series: Cell Reports
• Subjects: lamins; progeria; interferon response; replication stress; calcitriol; reprogramming
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124718301542

Summary: 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.