Repair of telomeric DNA prior to replicative senescence
Repair of telomeric DNA prior to replicative senescence
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DOI：
10.1016/s0047-6374(00)00151-2
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发表时间：
2000-09-01
影响因子：
5.3
通讯作者：
Lansdorp, PM
中科院分区：
文献类型：
--
作者：
Lansdorp, PM
在大多数正常的人类体细胞中，染色体末端的端粒重复序列的平均长度随着每次细胞分裂而减少50-200个碱基对。端粒重复序列的丢失与复制性衰老有因果关系，因为端粒酶的过度表达可以导致端粒的延长或维持以及具有二倍体和明显正常核型的体细胞的永生化。剩下的主要问题是端粒缩短诱导复制性衰老的实际机制，以及端粒缩短和复制性衰老在更新组织和衰老的细胞内稳态中的重要性。这种观点关注的是端粒缩短在个体细胞中的个体染色体上的后果。实验证据表明，短端粒积累衰老之前，复制性衰老不是由第一个端粒达到临界最小阈值长度触发。这些观察结果与端粒依赖性或端粒独立性DNA修复途径对短端粒的有限修复是相容的。端粒修复缺陷可能导致加速衰老和老化以及促进恶性转化的遗传不稳定性。在复制性衰老之前可能在端粒DNA修复中起作用的分子的实例包括ATM、p53、PARP、DNA-PK、Ku 70/80、人hRad 50-hMre 11-p95复合物、BRCA 1和2以及与布卢姆和沃纳综合征有关的解旋酶。(C)2000爱思唯尔科学爱尔兰有限公司保留所有权利。
The average length of telomere repeats at the ends of chromosomes in most normal human somatic cells has been found to decrease by 50-200 base pairs with each cell division. The loss of telomere repeats has been causally linked to replicative senescence by the demonstration that overexpression of the enzyme telomerase can result in the elongation or maintenance of telomeres and immortalization of somatic cells with a diploid and apparently normal karyotype. Major questions that remain are related to the actual mechanism by which telomere shortening induces replicative senescence and the importance of telomere shortening and replicative senescence in the homeostasis of cells in renewal tissues and aging. This perspective is concerned with the consequences of telomere shortening at individual chromosomes in individual cells. Experimental evidence indicates that short telomeres accumulate prior to senescence and that replicative senescence is not triggered by the first telomere to reach a critical minimal threshold length. These observations are compatible with limited repair of short telomeres by telomerase-dependent or telomerase-independent DNA repair pathways. Deficiencies in telomere repair may result in accelerated senescence and aging as well as genetic instability that facilitates malignant transformation. Examples of molecules that may have a role in the repair of telomeric DNA prior to replicative senescence include ATM, p53, PARP, DNA-PK, Ku70/80, the human hRad50-hMre11-p95 complex, BRCA 1 and 2 and the helicases implicated in Bloom's and Werner's syndrome. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.