Centromere defects, chromosome instability, and cGAS-STING activation in systemic sclerosis

Souren Paul, Mark H. Kaplan, Dinesh Khanna, Preston M. McCourt, Anjan K. Saha, Pei-Suen Tsou, Mahek Anand, Alexander Radecki, Mohamad Mourad, Amr H. Sawalha, David M. Markovitz () and Rafael Contreras-Galindo ()
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Souren Paul: University of Minnesota
Mark H. Kaplan: University of Michigan
Dinesh Khanna: University of Michigan
Preston M. McCourt: University of Minnesota
Anjan K. Saha: University of Michigan
Pei-Suen Tsou: University of Michigan
Mahek Anand: University of Minnesota
Alexander Radecki: University of Michigan
Mohamad Mourad: University of Michigan
Amr H. Sawalha: University of Michigan
David M. Markovitz: University of Michigan
Rafael Contreras-Galindo: University of Minnesota

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Centromere defects in Systemic Sclerosis (SSc) have remained unexplored despite the fact that many centromere proteins were discovered in patients with SSc. Here we report that lesion skin fibroblasts from SSc patients show marked alterations in centromeric DNA. SSc fibroblasts also show DNA damage, abnormal chromosome segregation, aneuploidy (only in diffuse cutaneous (dcSSc)) and micronuclei (in all types of SSc), some of which lose centromere identity while retaining centromere DNA sequences. Strikingly, we find cytoplasmic “leaking” of centromere proteins in limited cutaneous SSc (lcSSc) fibroblasts. Cytoplasmic centromere proteins co-localize with antigen presenting MHC Class II molecules, which correlate precisely with the presence of anti-centromere antibodies. CENPA expression and micronuclei formation correlate highly with activation of the cGAS-STING/IFN-β pathway as well as markers of reactive oxygen species (ROS) and fibrosis, ultimately suggesting a link between centromere alterations, chromosome instability, SSc autoimmunity, and fibrosis.

Date: 2022
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DOI: 10.1038/s41467-022-34775-8

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