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

Abstract

SUMMARYHutchinson-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.

Calcitriol Prevents RAD51 Loss and cGAS‐STING‐IFN Response Triggered by Progerin

“…Our previous studies revealed that calcitriol treatment ameliorates many of the aging phenotypes in progerin‐expressing cells, including DNA damage and RS . Here, we find that pre‐treatment of HDFs with calcitriol for 2 days prior to induction of progerin completely prevents the RFI observed 48 h after doxycycline treatment (Figure 1C).…”

“…To understand the molecular mechanisms underlying RS in progerin‐expressing cells, and the mechanisms responsible for the rescue by calcitriol, we monitored the levels of factors with a known role in RF stability and DNA repair. First, we re‐analyzed our published RNAseq studies performed in HGPS patient derived fibroblasts proliferating in culture for 3 months (accession number: GSE97986) to monitor levels of expression of DNA repair/replication factors. This analysis revealed downregulation of a variety of factors in the BRCA pathway with respect to normal fibroblasts from parents of HGPS patients ( Figure 2A).…”

“…Progerin causes downregulation of RAD51. A) Re‐analysis of published RNAseq data performed in five lines of normal fibroblasts (NF) and three lines of HGPS patient‐derived fibroblasts growing in culture for 90 days (accession # GSE97986). Expression of DNA repair genes shows a decrease in the BRCA pathway.…”

“…Our previous studies in progerin‐expressing cells revealed accumulation of DNA damage and replication stress (RS) . In fact, the replication defects in progerin‐expressing cells are more robust than in lamin‐depleted cells, causing replication fork (RF) stalling in addition to fork degradation by nucleases .…”

“…In addition, we found that forks are susceptible to Mre11 nuclease‐mediated degradation in progerin‐expressing cells. As such, inhibition of Mre11 nuclease activity by mirin rescues RF instability (RFI) . This suggests that progerin might hinder not only replication fork progression by eliciting the mislocalization of replisome factors such as PCNA and RFC, but also the proper recruitment of RF protective factors during instances of RS.…”