A Cell-Intrinsic Interferon-like Response Links Replication Stress to Cellular Aging Caused by Progerin
Ray Kreienkamp,
Simona Graziano,
Nuria Coll-Bonfill,
Gonzalo Bedia-Diaz,
Emily Cybulla,
Alessandro Vindigni,
Dale Dorsett,
Nard Kubben,
Luis Francisco Zirnberger Batista,
Susana Gonzalo
Affiliations
Ray Kreienkamp
Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA
Simona Graziano
Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA
Nuria Coll-Bonfill
Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA
Gonzalo Bedia-Diaz
Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA
Emily Cybulla
Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA
Alessandro Vindigni
Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA
Dale Dorsett
Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA
Nard Kubben
National Cancer Institute, NIH, Bethesda, MD 20892, USA
Luis Francisco Zirnberger Batista
Departments of Medicine and Developmental Biology, Washington University, 660 S. Euclid Ave., St. Louis, MO 63110, USA
Susana Gonzalo
Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA; Corresponding author
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.