Telomere dysfunction as a cause of genomic instability in Werner syndrome
Telomere dysfunction as a cause of genomic instability in Werner syndrome
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DOI：
10.1073/pnas.0609410104
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发表时间：
2007-02-13
影响因子：
11.1
通讯作者：
Karlseder, Jan
中科院分区：
文献类型：
--
作者：
Crabbe, Laure;Jauch, Anna;Karlseder, Jan
沃纳综合征（WS）是一种罕见的人类早衰疾病，由编码RecQ解旋酶WRN的基因突变引起。除了衰老特征外，这种疾病还以基因组不稳定为标志，并与癌症发病率升高相关。多条证据表明端粒功能障碍与该综合征的衰老表型有关；然而，WS细胞中观察到的基因组不稳定的根源以及WS癌症高发的原因尚未确定。我们先前提出，WRN解旋酶活性对于防止DNA复制过程中端粒的急剧丢失是必要的。在此我们证明，与复制相关的端粒丢失是导致在WS成纤维细胞中发现的染色体融合的原因。此外，通过中期分析我们表明，端粒酶介导的端粒延长可显著减少缺乏WRN的细胞中新的染色体畸变的出现，这类似于用WRN对WS细胞进行互补。我们的结果表明，WS细胞中的基因组不稳定直接取决于端粒功能障碍，将这种疾病中的染色体末端维持与染色体畸变联系起来。
Werner syndrome (WS) is a rare human premature aging disease caused by mutations in the gene encoding the RecQ helicase WRN. In addition to the aging features, this disorder is marked by genomic instability, associated with an elevated incidence of cancer. Several lines of evidence suggest that telomere dysfunction is associated with the aging phenotype of the syndrome; however, the origin of the genomic instability observed in WS cells and the reason for the high incidence of cancer in WS have not been established. We previously proposed that WRN helicase activity was necessary to prevent dramatic telomere loss during DNA replication. Here we demonstrate that replication-associated telomere loss is responsible for the chromosome fusions found in WS fibroblasts. Moreover, using metaphase analysis we show that telomere elongation by telomerase can significantly reduce the appearance of new chromosomal aberrations in cells lacking WRN, similar to complementation of WS cells with WRN. Our results suggest that the genome instability in WS cells depends directly on telomere dysfunction, linking chromosome end maintenance to chromosomal aberrations in this disease.