Telomerase RNA level limits telomere maintenance in X-linked dyskeratosis congenita
Telomerase RNA level limits telomere maintenance in X-linked dyskeratosis congenita
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DOI：
10.1101/gad.1476206
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发表时间：
2006-10-15
影响因子：
10.5
通讯作者：
Collins, Kathleen
中科院分区：
文献类型：
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作者：
Wong, Judy M. Y.;Collins, Kathleen
与极短的端粒有关。DC的主要X-连锁形式由dyskerin中的取代产生，dyskerin是核糖体RNA（rRNA）假尿苷修饰和端粒酶RNA（TER）细胞积累所需的蛋白质。因此，替代模型已经假定，X连锁DC中细胞更新的耗尽是核糖体缺陷或端粒酶缺陷的主要结果。在这里，我们第一次测试X连锁DC患者细胞是否在端粒处的端粒酶功能受损。我们发现，端粒酶激活家族匹配的对照细胞允许端粒延长和端粒长度的维护，而端粒酶激活X-连锁的DC患者细胞不能防止端粒侵蚀与增殖。此外，我们通过表型拯救证明，X连锁DC患者细胞中的端粒缺陷仅由TER积累减少引起。我们还表明，避免过早衰老的X-连锁DC患者细胞支持rRNA假尿苷修饰的正常水平和rRNA前体加工的正常动力学，与针对人类疾病的拟议小鼠模型报道的表型相反。这些发现支持端粒酶缺陷在X连锁DC的病理学中的重要性。
correlating with critically short telomeres. The predominant X-linked form of DC results from substitutions in dyskerin, a protein required both for ribosomal RNA ( rRNA) pseudouridine modification and for cellular accumulation of telomerase RNA (TER). Accordingly, alternative models have posited that the exhaustion of cellular renewal in X-linked DC arises as a primary consequence of ribosome deficiency or telomerase deficiency. Here we test, for the first time, whether X-linked DC patient cells are compromised for telomerase function at telomeres. We show that telomerase activation in family-matched control cells allows telomere elongation and telomere length maintenance, while telomerase activation in X-linked DC patient cells fails to prevent telomere erosion with proliferation. Furthermore, we demonstrate by phenotypic rescue that telomere defects in X-linked DC patient cells arise solely from reduced accumulation of TER. We also show that X-linked DC patient cells averted from premature senescence support normal levels of rRNA pseudouridine modification and normal kinetics of rRNA precursor processing, in contrast with phenotypes reported for a proposed mouse model of the human disease. These findings support the significance of telomerase deficiency in the pathology of X-linked DC.