Molecular mechanisms of telomere biology disorders.
Molecular mechanisms of telomere biology disorders.
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DOI：
10.1074/jbc.rev120.014017
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Nandakumar J
中科院分区：
文献类型：
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作者：
Grill S;Nandakumar J
影响端粒酶功能或端粒维持的基因突变导致统称为端粒病的各种疾病。这种广泛的疾病，包括先天性角化不良、肺纤维化和再生障碍性贫血，其特征在于端粒严重短，在最严重的情况下通常导致造血干细胞衰竭。最近的工作集中在了解这些疾病的分子基础上。端粒酶催化亚基TERT和TR的突变会损害活性，而其他亚基，如端粒蛋白TPP1中发现的突变，会减少端粒酶向端粒的募集。突变的端粒酶相关蛋白TCAB1和dyskerin以及端粒酶RNA成熟组分poly（A）特异性核糖核酸酶影响端粒酶的成熟和稳定性。相比之下，CTC1或RTEL1中的疾病相关突变与端粒复制缺陷更广泛相关。然而，即使最近大量研究解码这些疾病的机制，很大一部分先天性角化不良突变仍然没有特征或知之甚少。在这里，我们回顾了目前的理解端粒病变的分子基础和突出的实验数据，说明如何在这些患者的基因突变驱动端粒缩短和功能障碍。这篇综述将临床和分子研究的见解联系起来，以全面了解驱动这些疾病的潜在机制。通过这一点，我们强调了治疗方法的最新进展，并查明了其作用机制仍不明确的疾病相关变异。最后，我们提出了未来的研究途径，这将加深我们对端粒生物学和端粒相关疾病的理解。
Genetic mutations that affect telomerase function or telomere maintenance result in a variety of diseases collectively called telomeropathies. This wide spectrum of disorders, which include dyskeratosis congenita, pulmonary fibrosis, and aplastic anemia, is characterized by severely short telomeres, often resulting in hematopoietic stem cell failure in the most severe cases. Recent work has focused on understanding the molecular basis of these diseases. Mutations in the catalytic TERT and TR subunits of telomerase compromise activity, while others, such as those found in the telomeric protein TPP1, reduce the recruitment of telomerase to the telomere. Mutant telomerase-associated proteins TCAB1 and dyskerin and the telomerase RNA maturation component poly(A)-specific ribonuclease affect the maturation and stability of telomerase. In contrast, disease-associated mutations in either CTC1 or RTEL1 are more broadly associated with telomere replication defects. Yet even with the recent surge in studies decoding the mechanisms underlying these diseases, a significant proportion of dyskeratosis congenita mutations remain uncharacterized or poorly understood. Here we review the current understanding of the molecular basis of telomeropathies and highlight experimental data that illustrate how genetic mutations drive telomere shortening and dysfunction in these patients. This review connects insights from both clinical and molecular studies to create a comprehensive view of the underlying mechanisms that drive these diseases. Through this, we emphasize recent advances in therapeutics and pinpoint disease-associated variants that remain poorly defined in their mechanism of action. Finally, we suggest future avenues of research that will deepen our understanding of telomere biology and telomere-related disease.