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Identifier

000412709

Title

Delineating the impact of deregulated SMC1A (Structural Maintenance of Chromosomes 1A) in the pathogenesis of Systemic Lupus Erythematosus.

Alternative Title

Διερεύνηση του ρόλου της πρωτεΐνης SMC1A (Structural Maintenance of Chromosomes 1A) στην παθογένεια του Συστηματικού Ερυθηματώδους Λύκου

Author

Κοσμαρά, Δέσποινα

Thesis advisor

Μπερτσιάς, Γεώργιος

Reviewer

Σιδηρόπουλος, Πρόδρομος
Χαμηλός, Γεώργιος

Abstract

A striking characteristic of Systemic Lupus Erythematosus (SLE), the prototype systemic autoimmune disease, is that it features a substantially greater frequency in females than in males (female:male ratio ranging from 7:1 to 15:1). By contrast, males – although less frequently afflicted – tend to suffer from more severe disease. We have recently completed a whole-blood RNA sequencing in SLE patients and matched healthy individuals in order to delineate the molecular basis of the disease. Further bioinformatics analysis was carried out to detect differentially expressed genes between the two genders in SLE versus healthy controls. A sex-biased molecular signature was unraveled, which was specifically associated with the disease. Among these genes, SMC1A (Structural Maintenance of Chromosomes 1A) exhibited the strongest gender bias with the greatest statistical significance. Specifically, SMC1A expression was significantly reduced in male SLE patients compared to female SLE patients and their healthy counterparts. SMC1A encodes for a structural component of cohesin complex and participates in sister chromatid cohesion and gene regulation via chromatin architecture remodeling. Importantly, SMC1A is also implicated in DNA damage repair network as its phosphorylation constitutes a critical downstream event for cell survival and chromosomal stability after DNA damage. Notably, it has been recently demonstrated that SLE lymphocytes are less efficient in repairing DNA damage leading to increased cell apoptosis and additionally have increased levels of DNA double-strand breaks (DSBs). Taking these into consideration, our aim was to delineate the role of deregulated SMC1Α in SLE susceptibility or severity and its potential implication in lupus sexual dimorphism by focusing on its role in DNA damage repair. SMC1A mRNA levels were found significantly reduced in purified CD4+ T lymphocytes from male SLE patients but they were also moderately reduced in female SLE patients. Additionally, SLE male CD4+ T cells appeared to have diminished phosphorylated SMC1A (pSMC1a) levels, in spite of increased levels of DSBs, compared to female SLE patients and their healthy counterparts. These results indicate a gender-biased (i.e. reduced in males) SMC1A expression in SLE and imply a defective activity of this protein in repairing DNA damage of male lupus CD4+ T cells. Further delineating the role of SMC1A in SLE pathogenesis could improve our understanding of how DNA damage is associated with the disease. Finally, it could potentially lead to novel targets of treatment tailored for males and females.

Language

English

Subject

Cohesin complex

DNA damage responce

Sexual dimorphism

Επιδιόρθωση βλαβών DNA

Σύμπλεγμα κοχεσίνης

Φυλετικός διμορφισμός

Issue date

2017-11-24

Collection