Dyskerin, telomerase and the DNA damage response
Dyskerin, telomerase and the DNA damage response
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DOI：
10.4161/cc.8.1.7265
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发表时间：
2009-01-01
期刊：
影响因子：
4.3
通讯作者：
Mason, Philip J.
中科院分区：
文献类型：
--
作者：
Gu, BaiWei;Bessler, Monica;Mason, Philip J.
先天性角化不良（DC）骨髓衰竭综合征虽然罕见，但在过去几年引起了广泛关注，因为它是由参与端粒维持的基因突变引起的。该疾病具有多种特征，这些特征都可能是由于需要通过干细胞活性不断更新的组织衰竭所致。人们认为这是由端粒维持缺陷引起的，最终导致细胞周期停滞或由端粒极短引起的细胞死亡。 DC 最常见的形式是 X 连锁形式，由编码核仁蛋白 Dyskerin 的 DKC1 突变引起。我们最近报道了一种 X 连锁疾病的小鼠模型，其中复制人类致病性突变的突变杂合的雌性小鼠在表达突变型 Dykerin 的细胞中表现出生长不利。这种生长劣势与 DNA 损伤反应增强有关，依赖于端粒酶，但似乎与端粒缩短无关。在这里，我们从 Dykerin 在端粒维持中的作用以及 DNA 损伤反应在 DC 发病机制中可能发挥的作用来讨论这些结果。
The bone marrow failure syndrome Dyskeratosis congenita (DC), though rare, has attracted a great deal of attention in the last few years because it is caused by mutations in genes whose products are involved in telomere maintenance. The disease presents with a variety of features that can all be due to failure of tissues that require constant renewal via stem cell activity. It is thought this is caused by defects in telomere maintenance leading eventually to cell cycle arrest or cell death caused by critically short telomeres. The most common form of DC is the X-linked form caused by mutations in DKC1 encoding the nucleolar protein, dyskerin. We recently reported a mouse model of the X-linked form of the disease in which females heterozygous for a mutation that copies a human pathogenic mutation showed a growth disadvantage in cells expressing the mutant dyskerin. This growth disadvantage, which was associated with an enhanced DNA damage response, was dependent on telomerase but appeared to be independent of telomere shortening. Here we discuss these results in terms of the role of dyskerin in telomere maintenance and the possible role that the DNA damage response plays in the pathogenesis of DC.