Cell Reports (Feb 2018)

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

DOI
https://doi.org/10.1016/j.celrep.2018.01.090
Journal volume & issue
Vol. 22, no. 8
pp. 2006 – 2015

Abstract

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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.

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