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    Decrease in RNase HII and Accumulation of lncRNAs/DNA Hybrids: A Causal Implication in Psoriasis
    (MDPI, 2022) Mehmetbeyoğlu, Ecmel; Kianmehr, Leila; Borlu, Murat; Yılmaz, Zeynep; Kılıç, Şeyma Başar; Rajabi-Maham, Hassan; Taheri, Serpil; Rassoulzadegan, Minoo
    Functional long non-coding RNAs (lncRNAs) have been in the limelight in aging research because short telomeres are associated with higher levels of TERRA (Telomeric Repeat containing RNA). The genomic instability, which leads to short telomeres, is a mechanism observed in cell aging and in a class of cancer cells. Psoriasis, a skin disease, is a disorder of epidermal keratinocytes, with altered telomerase activity. Research on the fraction of nascent RNAs in hybrid with DNA offers avenues for new strategies. Skin and blood samples from patients were fractionated to obtain the RNA associated with DNA as a R-loop structure. The higher amount of TERRA levels attached with each chromosome end was found with psoriasis patients in blood and skin. In addition to telomeric TERRA, we evidenced accumulation of others non-coding RNA, such as non-telomeric TERRA and centromeric transcripts. Increased levels of non-coding RNAs attached to DNA correlates with a decreased in Ribonuclease HII (RNase-HII) transcript which means that overall unresolved DNA–RNA hybrids can ultimately weaken DNA and cause skin lesions. Since the genome is actively transcribed, cellular RNase-HII is essential for removing RNA from the DNA–RNA hybrid in controls of genome stability and epigenome shaping and can be used as a causal prognostic marker in patients with psoriasis.
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    Psoriatic skin transcript phenotype: androgen/estrogen and cortisone/ cortisol imbalance with increasing DNA damage response
    (Springer Science and Business Media B.V., 2024) Başar Kılıç, Şeyma; Taheri, Serpil; Mehmetbeyoğlu Duman, Ecmel; Öksüm Solak, Eda; Yılmaz Şükranlı, Zeynep; Rassoulzadegan, Minoo; Borlu, Murat
    Patients prone to psoriasis suffer after a breakdown of the epidermal barrier and developpoorly healing lesions with abnormal proliferation of keratinocytes. Strong inflammatory reactions withgenotoxicity (short telomeres) suggest impaired immune defenses with DNA damage repair response(DDR) in patients with psoriasis. Recent evidence indicates the existence of crosstalk mechanismslinking the DDR machinery and hormonal signaling pathways that cooperate to influence bothprogressions of many diseases and responses to treatment. The aim of this study was to clarify whethersteroid biosynthesis and genomic stability markers are altered in parallel during the formation ofpsoriatic skin. Understanding the interaction of the steroid pathway and DNA damage response iscrucial to addressing underlying fundamental issues and managing resulting epidermal barrierdisruption in psoriasis. Methods: Skin (Lesional, non-lesional) and blood samples from twenty psoriasis patients and fifteen healthy volunteers were collected. Real-Time-PCR study was performed to assess levels of known transcripts such as: estrogen (ESR1, ESR2), androgen (AR), glucocorticoid/mineralocorticoid receptors (NR3C1, NR3C2), HSD11B1/HSD11B2, and DNA damage sensors (SMC1A, TREX1, TREX2, SSBP3, RAD1, RAD18, EXO1, POLH, HUS1). Results: We found that ESR1, ESR2, HSD11B1, NR3C1, NR3C2, POLH, and SMC1A transcripts were significantly decreased and AR, TREX1, RAD1, and SSBP3 transcripts were increased dramatically in the lesional skin compared to skin samples of controls. Conclusion: We found that the regulation of the steroidogenic pathway was disrupted in the lesional tissue of psoriasis patients and that a sufficient glucocorticoid and mineralocorticoid response did not form and the estrogen/androgen balance was altered in favour of androgens. We suggest that an increased androgen response in the presence of DDR increases the risk of developing psoriasis. Although this situation may be the cause or the consequence of a disruption of the epidermal barrier, our data suggest developing new therapeutic strategies.