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.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9674829 | PMC |
http://dx.doi.org/10.1038/s41467-022-34775-8 | DOI Listing |
Nat Commun
December 2024
Department of Medicine, Columbia Center for Human Development and Stem Cell Therapies, Columbia University Irving Medical Center, New York, NY, USA.
Pluripotent stem cells possess a unique nuclear architecture characterized by a larger nucleus and more open chromatin, which underpins their ability to self-renew and differentiate. Here, we show that the nucleolus-specific RNA helicase DDX18 is essential for maintaining the pluripotency of human embryonic stem cells. Using techniques such as Hi-C, DNA/RNA-FISH, and biomolecular condensate analysis, we demonstrate that DDX18 regulates nucleolus phase separation and nuclear organization by interacting with NPM1 in the granular nucleolar component, driven by specific nucleolar RNAs.
View Article and Find Full Text PDFNucleic Acids Res
December 2024
Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) OT Gatersleben, Corrensstr 3, 06466 Seeland, Germany.
In eukaryotes, accurate chromosome segregation during cell division relies on the centromeric histone H3 variant, CENH3. Our previous work identified KINETOCHORE NULL2 (αKNL2) as a plant CENH3 assembly factor, which contains a centromere-targeting motif, CENPC-k, analogous to the CENPC motif found in CENP-C. We also demonstrated that αKNL2 can bind DNA in vitro in a sequence-independent manner, without the involvement of its CENPC-k motif.
View Article and Find Full Text PDFNat Commun
December 2024
Department of Meiosis, Max Planck Institute for Multidisciplinary Sciences, Göttingen, Germany.
Aneuploidy in eggs is a leading cause of miscarriages or viable developmental syndromes. Aneuploidy rates differ between individual chromosomes. For instance, chromosome 21 frequently missegregates, resulting in Down Syndrome.
View Article and Find Full Text PDFCell Biol Toxicol
December 2024
Department of Neurosurgery, Peking University First Hospital, No. 8 Xishiku Street, Xicheng District, Beijing, 100034, China.
Centromere protein M (CENPM), traditionally associated with chromosome segregation, is now recognized for its significant role in cancer biology. Particularly in glioblastoma (GBM), where less is known about CENPM compared to other centromere proteins (CENPs), it appears crucially involved in regulating tumor cell proliferation, invasion, and metabolic reprogramming-key factors in GBM's aggressiveness. Initial analyses using the GEPIA database (TCGA/GTEx datasets) reveal distinct patterns of CENPM expression in GBM, suggesting its potential as a therapeutic target.
View Article and Find Full Text PDFNucleic Acids Res
December 2024
School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong SAR, China.
Incomplete sister centromere decatenation results in centromeric ultrafine anaphase bridges (UFBs). PICH (PLK1-interacting checkpoint helicase), a DNA translocase, plays a crucial role in UFB resolution by recruiting UFB-binding proteins and stimulating topoisomerase IIα. However, the involvement of distinct PICH functions in UFB resolution remains ambiguous.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!