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

Cell Rep. 2018 Feb 20;22(8):2006-2015. doi: 10.1016/j.celrep.2018.01.090.


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.

Keywords: calcitriol; interferon response; lamins; progeria; replication stress; reprogramming.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Calcitriol / pharmacology
  • Cytosol / metabolism
  • DNA / metabolism
  • DNA Replication*
  • Fibroblasts / drug effects
  • Fibroblasts / metabolism
  • Fibroblasts / pathology
  • Humans
  • Interferons / metabolism*
  • Lamin Type A / metabolism*
  • Mice
  • Phenotype
  • Progeria / metabolism
  • Receptors, Pattern Recognition / metabolism
  • STAT1 Transcription Factor / metabolism
  • Stress, Physiological*


  • Lamin Type A
  • Receptors, Pattern Recognition
  • STAT1 Transcription Factor
  • prelamin A
  • DNA
  • Interferons
  • Calcitriol