背景:端粒病是一组遗传性疾病,由涉及端粒维持的基因中的种系致病变异引起,导致过度的端粒磨损,影响几种组织,包括造血.RecQ和RTEL1解旋酶通过解链端粒结构如G-四链体(G4)有助于端粒维持,防止复制缺陷。种系RTEL1变异也是端粒病的病因。
结果:在这里,我们研究了RecQ的表达(RECQL1,BLM,WRN,人类端粒病患者外周血单核细胞(PBMC)中的RECQL4和RECQL5)和RTEL1解旋酶基因。所有RecQ解旋酶的mRNA表达水平,而不是RTEL1,在患者的原代细胞中显著下调。RecQ表达降低不是由于细胞增殖耗竭,因为RecQ解旋酶在体外耗尽的T细胞中没有减弱。另外15个参与DNA损伤修复和RecQ功能伴侣的基因也在端粒病细胞中下调。
结论:这些研究结果表明,RecQ解旋酶和参与DNA修复的功能伴侣的表达在端粒病患者的PBMC中下调。
BACKGROUND: Telomeropathies are a group of inherited disorders caused by germline pathogenic variants in genes involved in telomere maintenance, resulting in excessive telomere attrition that affects several tissues, including hematopoiesis. RecQ and RTEL1 helicases contribute to telomere maintenance by unwinding telomeric structures such as G-quadruplexes (G4), preventing replication defects. Germline RTEL1 variants also are etiologic in telomeropathies.
RESULTS: Here we investigated the expression of RecQ (RECQL1, BLM, WRN, RECQL4, and RECQL5) and RTEL1 helicase genes in peripheral blood mononuclear cells (PBMCs) from human telomeropathy patients. The mRNA expression levels of all RecQ helicases, but not RTEL1, were significantly downregulated in patients\' primary cells. Reduced RecQ expression was not attributable to cell proliferative exhaustion, as RecQ helicases were not attenuated in T cells exhausted in vitro. An additional fifteen genes involved in DNA damage repair and RecQ functional partners also were downregulated in the telomeropathy cells.
CONCLUSIONS: These findings indicate that the expression of RecQ helicases and functional partners involved in DNA repair is downregulated in PBMCs of telomeropathy patients.