Fig. 9: The model depicting how centromere alterations and chromosome instability could impact the etiology of Systemic Sclerosis.
From: Centromere defects, chromosome instability, and cGAS-STING activation in systemic sclerosis
The damage to skin fibroblasts leads to centromere DNA alterations and/or abnormal centromere protein deposition in the cytoplasm. In dcSSc, centromere damage produces centromeric contractions and reduction of CENPA deposition at the centromere, leading to unstable kinetochore and microtubule attachment. These processes result in chromosome instability (CIN), characterized by aneuploidy and micronuclei formation and upregulation of CENPA. The overexpression of and/or mislocalization of CENPA alters gene expression as we have seen in cancer45. In lcSSc, altered deposition of CENP proteins leads to CIN characterized by micronuclei formation as well as to excess of CENPA deposition. In lcSSc patients who develop ACAs, centromere DNA is somewhat affected and centromere proteins leak into the cytoplasm, further increasing the level of CENPA expression, which further drives CIN characterized by micronuclei formation. Given that fibroblasts from patients with SSc are known to express MHC on their surface, these MHC molecules likely present the cytoplasmic CENPs to B cells to induce production of ACAs. The presence of extranuclear DNA (micronuclei) in all SSc fibroblasts leads to activation of the cGAS-STING/IFN-β pathway and autoimmunity. DSBs doubled-strand breaks, IFN-β interferon beta, IL6 interleukin 6, CENP centromere protein, MHC major histocompatibility complex.
