Telomere length, aging, and somatic cell turnover.
Telomere length, aging, and somatic cell turnover.
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端粒长度，衰老和体细胞更新。
DOI：
10.1084/jem.190.2.153
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发表时间：
1999-07-19
影响因子：
15.3
通讯作者：
Hodes, R J
中科院分区：
文献类型：
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作者：
Hodes, R J
端粒是一种独特的蛋白质-DNA结构，包括真核线性染色体的末端（综述见参考文献1，2）。端粒DNA不包含蛋白质编码基因，而是由富含G的六核苷酸重复序列组成，在脊椎动物细胞中是（TTAGGG）n序列。基于最初在酵母和其他单细胞生物中进行的研究，似乎端粒的功能包括稳定和保护染色体末端免受诸如非法重组、确定细胞核内染色体定位以及调节细胞复制能力等事件的影响。正是这最后一个功能，端粒在调节复制能力中的作用，在细胞衰老和有机体衰老的研究中受到了特别的关注。理解体细胞生物学的一个关键发现是观察到正常体细胞具有有限的复制寿命（3）。也就是说，它们能够进行有限数量的细胞分裂，之后它们经历所谓的复制性衰老，并且不能进一步细胞分裂。监测这一过程的复制时钟的机制引起了人们的极大关注，正是在这种背景下，端粒的功能引起了人们特别强烈的兴趣。将端粒功能与细胞衰老和复制性衰老相关联的最广泛接受的范例是基于在正常体细胞中端粒随着每次细胞分裂而缩短的观察（4，5）。这种端粒缩短归因于染色体复制过程中DNA合成的引物需求，并导致每次细胞分裂时不完全复制和末端端粒重复序列的丢失（6）。因此，端粒随着连续的细胞分裂而逐渐缩短，体细胞中的端粒长度因此可以反映该细胞谱系的复制历史。原则上，这是一个潜在的强大的工具，用于分析细胞分裂的生理情况下，否则很难监测体内克隆扩增。因此，端粒长度的测量已被广泛用于分析谱系或染色体-产物关系以及细胞分裂速率。然而，在解释端粒长度变化的意义时，关键是要考虑在任何时间点可能影响端粒净长度的多种因素。体细胞中端粒长度的起点是个体生殖系细胞中端粒的长度。
Telomeres are unique protein–DNA structures that com-prise the termini of eukaryotic linear chromosomes (for review see references 1, 2). Telomeric DNA does not contain protein-encoding genes but rather consists of G-rich hexanucleotide repeats that in vertebrate cells are (TTAGGG) n sequences. Based on studies initially carried out in yeast and other single cell organisms, it appears that telomere functions include the stabilization and protection of chromosomal ends from events such as illegitimate recombination, the determination of chromosomal localization within the nucleus, and the regulation of cellular replicative capacity. It is this last function, the role of telomeres in regulation of replicative capacity, that has received particular attention in studies of cellular senescence and organismal aging. A pivotal finding in the understanding of somatic cell biology was the observation that normal somatic cells have a finite replicative life span (3). That is, they are capable of a finite number of cell divisions, after which they undergo what has been termed replicative senescence and are incapable of further cell division. The mechanism underlying the replicative clock that monitors this process has evoked considerable attention, and it is in this context that telomere function has been of particularly intense interest. The most widely accepted paradigm relating telomere function to cellular aging and replicative senescence is based on the observation that in normal somatic cells telomeres shorten with each cell division (4, 5). This telomere shortening has been attributed to the primer requirement for DNA synthesis during chromosomal replication, and results in incomplete replication and a loss of terminal telomeric repeats with each cell division (6). Telomeres thus shorten progressively with successive cell divisions, and telomere length in a somatic cell may thus reflect the replicative history of that cellular lineage. In principle, this is a potentially powerful tool for the analysis of cell division under physiologic circumstances in which it is otherwise very difficult to monitor in vivo clonal expansion. For this reason, measurement of telomere length has been widely used to analyze lineage or precursor–product relationships and rates of cell division.However, in interpreting the significance of changes in telomere length, it is critical to consider the multiple factors that may influence the net length of telomeres at any point in time. The starting point for telomere length in somatic cells is the length of telomeres in germ line cells of the indi-