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

Cell Reports
Ray KreienkampSusana Gonzalo

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.

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Citations

Dec 14, 2019·Proteomics·Nuria Coll-BonfillSusana Gonzalo
Feb 6, 2020·Nature Reviews. Molecular Cell Biology·Weiqi ZhangJuan Carlos Izpisua Belmonte
Feb 13, 2020·Cells·Ray Kreienkamp, Susana Gonzalo
Jan 15, 2020·Nature Medicine·Sara AhadiMichael Snyder
Dec 15, 2018·Aging Cell·Ray KreienkampSusana Gonzalo
Jul 31, 2019·Nature Reviews. Genetics·Mona MotwaniKatherine A Fitzgerald
Mar 29, 2020·Clinical Science·Michael SchuligaDarryl A Knight
Nov 8, 2018·International Journal of Molecular Sciences·Shibani MukherjeeAroumougame Asaithamby
Jun 4, 2019·Frontiers in Genetics·Vasily V AshapkinIgor I Kireev
Jul 8, 2019·GeroScience·Susana Gonzalo, Nuria Coll-Bonfill
Aug 18, 2018·Frontiers in Oncology·Praveen KogantiMichael Blank
Oct 9, 2020·Cold Spring Harbor Molecular Case Studies·Nobuyuki TakahashiAnish Thomas
Jun 24, 2020·Molecular Cancer Research : MCR·Ikrame LazarZe'ev A Ronai
Jan 5, 2021·Aging Cell·Stefano SquarzoniGiovanna Lattanzi
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Jan 30, 2021·ELife·Karl N MillerMaria Grazia Vizioli
May 25, 2020·Ageing Research Reviews·Vittoria CenniGiovanna Lattanzi
Mar 4, 2021·Trends in Immunology·Brandon L Walling, Philip M Murphy
May 1, 2021·Genes·Simon WillaumePascale Bertrand
Jul 10, 2021·Ageing Research Reviews·Michael SchuligaDarryl A Knight
Aug 13, 2021·Frontiers in Cardiovascular Medicine·Lavinia Rech, Peter P Rainer
Jan 13, 2022·Aging·Christina ManakanatasSelma Osmanagic-Myers

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