Centromere Instability Drives Chromosome Damage and Autoantigen Exposure in Systemic Sclerosis.

Area of Science:

• Cell Biology
• Genetics
• Immunology

Background:

• Centromere breakage is linked to anti-centromere antibodies in systemic sclerosis (SSc).
• The origins of centromere damage and its connection to immune activation in SSc are not fully understood.
• The bleomycin-induced fibrosis model is a key experimental system for studying SSc.

Purpose of the Study:

• To investigate if bleomycin selectively disrupts centromeres.
• To determine if bleomycin-induced centromere damage contributes to chromosome instability.
• To explore the link between centromere damage and immunogenic chromatin mislocalization.

Main Methods:

• Evaluation of centromere integrity and genome damage responses in a bleomycin mouse model, human fibroblasts, and SSc patient fibroblasts.
• Assessment of centromeric α-satellite copy number, DNA damage/repair markers (γH2AX, RAD51), micronuclei, and nuclear envelope rupture.
• Immunofluorescence microscopy to analyze centromeric chromatin colocalization with antigen presentation machinery (HLA-DRB1).

Main Results:

• Bleomycin caused selective depletion of α-satellite repeats at centromeres and double-strand breaks at active centromeres (CENP-A marked).
• Persistent centromere loss occurred despite ATM-dependent, RAD51-mediated repair, indicating incomplete restoration.
• Increased micronuclei, cytoplasmic centromeric foci, and nuclear envelope rupture were observed, alongside CENP-B colocalization with HLA-DRB1, suggesting antigen presentation from centromeric chromatin.

Conclusions:

• Active centromeres are vulnerable targets of bleomycin-induced DNA damage with incomplete repair.
• Centromere instability leads to mislocalized chromatin that can engage antigen-presentation pathways.
• These findings offer mechanistic insights into SSc autoantibody specificity and link genome instability to immune activation in fibrotic autoimmunity.