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. 2021 Apr 9;12(4):552. doi: 10.3390/genes12040552

Figure 8.

Figure 8

Progerin expression in HGPS leads to DNA repair defect, replicative stress, and inflammation through DNA sensing in the cytosol. Expression of Progerin and the ensuing genomic instability has recently been reported to contribute to the activation cGAS-STING pathway and the production of an inflammatory response that may accelerate the aging process in HGPS cells. Indeed, Progerin accumulation leads to replicative stress by the sequestration of PCNA, away from the fork, and aberrant recruitment of XPA to stalled fork, which impedes their RAD51-dependent protection leading to degradation of stalled fork by MRE11. HGPS cells present an important accumulation of DNA damage due in part to the decreased level of VDR caused by Progerin which leads to a diminution of key DNA repair factor such as RAD51, BRCA1 (leading likely an HR defect) and 53BP1. Recently, it was reported that a calcitriol treatment could reduce the effect of Progerin accumulation on the VDR level, thus partially rescuing DSB repair mechanism in HGPS cells. It has also been shown altered histone modifications in Progerin accumulating cells, leading to reduced level of H3K9me3 in G0/G1 cells, inducing a defective ATM activation and defective amplification of the γH2AX signal in response to the DSBs and an impaired recruitment of 53BP1 and RIF1 during NHEJ. In contrast, it has been also reported (in early passage), an increase of SUV39 protein and H3K9me3; the condensed chromatin preventing access to DNA repair factors lead to persistent DNA damage. Depletion of SUV39 H1 rescue the DNA repair factor recruitment. As described previously, replicative stress and DNA damage accumulation (through the different mechanisms described here) can lead to cytosolic DNA production, which activate the cGAS-STING pathway and production of inflammatory factors. Moreover, Progerin accumulation has been reported to increase proteins levels of cGAS, STING, and PRRs and induce a IFN-like response mediated by STAT1. As a result, Progerin cells show an increased level of ISG.