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

Author

Listed:
  • Souren Paul

    (University of Minnesota)

  • Mark H. Kaplan

    (University of Michigan)

  • Dinesh Khanna

    (University of Michigan
    University of Michigan)

  • Preston M. McCourt

    (University of Minnesota)

  • Anjan K. Saha

    (University of Michigan
    University of Michigan
    University of Michigan)

  • Pei-Suen Tsou

    (University of Michigan
    University of Michigan)

  • Mahek Anand

    (University of Minnesota)

  • Alexander Radecki

    (University of Michigan)

  • Mohamad Mourad

    (University of Michigan)

  • Amr H. Sawalha

    (University of Michigan
    University of Pittsburgh School of Medicine)

  • David M. Markovitz

    (University of Michigan
    University of Michigan
    University of Michigan
    University of Michigan)

  • Rafael Contreras-Galindo

    (University of Minnesota
    University of Minnesota)

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.

Suggested Citation

  • 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 & Rafael Cont, 2022. "Centromere defects, chromosome instability, and cGAS-STING activation in systemic sclerosis," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34775-8
    DOI: 10.1038/s41467-022-34775-8
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    References listed on IDEAS

    as
    1. Weiguo Zhang & Jian-Hua Mao & Wei Zhu & Anshu K. Jain & Ke Liu & James B. Brown & Gary H. Karpen, 2016. "Centromere and kinetochore gene misexpression predicts cancer patient survival and response to radiotherapy and chemotherapy," Nature Communications, Nature, vol. 7(1), pages 1-15, November.
    2. Emma Bolderson & Joshua T. Burgess & Jun Li & Neha S. Gandhi & Didier Boucher & Laura V. Croft & Samuel Beard & Jennifer J. Plowman & Amila Suraweera & Mark N. Adams & Ali Naqi & Shu-Dong Zhang & Davi, 2019. "Barrier-to-autointegration factor 1 (Banf1) regulates poly [ADP-ribose] polymerase 1 (PARP1) activity following oxidative DNA damage," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    3. Karen H. Miga & Sergey Koren & Arang Rhie & Mitchell R. Vollger & Ariel Gershman & Andrey Bzikadze & Shelise Brooks & Edmund Howe & David Porubsky & Glennis A. Logsdon & Valerie A. Schneider & Tamara , 2020. "Telomere-to-telomere assembly of a complete human X chromosome," Nature, Nature, vol. 585(7823), pages 79-84, September.
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