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.
Original language | English (US) |
---|---|
Article number | 7074 |
Journal | Nature communications |
Volume | 13 |
Issue number | 1 |
DOIs | |
State | Published - Dec 2022 |
Bibliographical note
Funding Information:The authors are grateful to Drs. Gil Omenn, John Varga, and Harmit Malik for discussions. Grant 05–5089 from the Concerned Parents for AIDS Research (CPFA) supported M.H.K. The Michigan Science Training Program grant 5T32GM007863-34 and a University of Michigan Cancer Biology Fellowship supported A.K.S. NIH/NIAMS grant K24-AR063120-10 supported D.K. A generous donation from David and Jill Kurtz, a grant from the Rheumatology Research Foundation, and NIH grant RO1-CA-144043 supported D.M.M. The Hormel Institute, the Rheumatology Research Foundation, an NIH/NCI grant R21-CA259630, and the National Scleroderma Foundation supported R.C.-G. R.C.-G. is the recipient of the Mark Flapan Award from the National Scleroderma Foundation.
Publisher Copyright:
© 2022, The Author(s).