IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v13y2022i1d10.1038_s41467-022-34775-8.html
   My bibliography  Save this article

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
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-022-34775-8
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-022-34775-8?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    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.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Zhikun Wu & Zehang Jiang & Tong Li & Chuanbo Xie & Liansheng Zhao & Jiaqi Yang & Shuai Ouyang & Yizhi Liu & Tao Li & Zhi Xie, 2021. "Structural variants in the Chinese population and their impact on phenotypes, diseases and population adaptation," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    2. Kunpeng Li & Peng Xu & Jinpeng Wang & Xin Yi & Yuannian Jiao, 2023. "Identification of errors in draft genome assemblies at single-nucleotide resolution for quality assessment and improvement," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Mohamed Awad & Xiangchao Gan, 2023. "GALA: a computational framework for de novo chromosome-by-chromosome assembly with long reads," Nature Communications, Nature, vol. 14(1), pages 1-11, December.
    4. Tobias T. Schmidt & Carly Tyer & Preeyesh Rughani & Candy Haggblom & Jeffrey R. Jones & Xiaoguang Dai & Kelly A. Frazer & Fred H. Gage & Sissel Juul & Scott Hickey & Jan Karlseder, 2024. "High resolution long-read telomere sequencing reveals dynamic mechanisms in aging and cancer," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    5. Joanna Hård & Jeff E. Mold & Jesper Eisfeldt & Christian Tellgren-Roth & Susana Häggqvist & Ignas Bunikis & Orlando Contreras-Lopez & Chen-Shan Chin & Jessica Nordlund & Carl-Johan Rubin & Lars Feuk &, 2023. "Long-read whole-genome analysis of human single cells," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    6. Sarah Morrison-Smith & Christina Boucher & Aleksandra Sarcevic & Noelle Noyes & Catherine O’Brien & Nazaret Cuadros & Jaime Ruiz, 2022. "Challenges in large-scale bioinformatics projects," Palgrave Communications, Palgrave Macmillan, vol. 9(1), pages 1-9, December.
    7. Gabriel E. Rech & Santiago Radío & Sara Guirao-Rico & Laura Aguilera & Vivien Horvath & Llewellyn Green & Hannah Lindstadt & Véronique Jamilloux & Hadi Quesneville & Josefa González, 2022. "Population-scale long-read sequencing uncovers transposable elements associated with gene expression variation and adaptive signatures in Drosophila," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    8. Xiao Luo & Xiongbin Kang & Alexander Schönhuth, 2022. "VeChat: correcting errors in long reads using variation graphs," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-34775-8. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.