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

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

Author information

1
Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA.
2
National Cancer Institute, NIH, Bethesda, MD 20892, USA.
3
Departments of Medicine and Developmental Biology, Washington University, 660 S. Euclid Ave., St. Louis, MO 63110, USA.
4
Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, USA. Electronic address: sgonzalo@slu.edu.

Abstract

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

PMID:
29466729
PMCID:
PMC5848491
DOI:
10.1016/j.celrep.2018.01.090
[Indexed for MEDLINE]
Free PMC Article

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