Mathematical modeling confirms the length-dependency of telomere shortening
Mathematical modeling confirms the length-dependency of telomere shortening
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DOI：
10.1016/j.mad.2004.03.007
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发表时间：
2004-06-01
影响因子：
5.3
通讯作者：
van Riel, NAW
中科院分区：
文献类型：
--
作者：
den Buijs, JO;van den Bosch, PPJ;van Riel, NAW
端粒是染色体的末端，在人体细胞中，由于末端复制问题、C链加工和氧化损伤，端粒随着每次细胞分裂而缩短。另一方面，逆转录酶端粒酶可以在端粒末端添加端粒重复序列。有人认为，一旦端粒达到临界长度，细胞就会停止增殖，也称为衰老。越来越多的证据表明，端粒缩短和随后的衰老可能在危及生命的疾病中起着至关重要的作用。到目前为止，数学模型将端粒缩短描述为一个自主过程，其中每次细胞分裂的损失不取决于端粒长度本身。在这项研究中，已发表的人成纤维细胞和人内皮细胞中端粒分布的测量结果被用来表明端粒以长度依赖性的方式缩短。随后，构建了端粒磨损的数学模型，其中引入了缩短因子和自主损失。据推测，衰老的百分比与端粒低于临界长度的百分比有关。该模型与已发表的端粒长度和衰老的人内皮细胞的数据进行了比较，使用最大似然法。这使得生理上重要的参数的估计，并确认端粒缩短的长度依赖性。(C)2004爱思唯尔爱尔兰有限公司保留所有权利。
Telomeres, the ends of chromosomes, shorten with each cell division in human somatic cells, because of the end-replication problem, C-strand processing and oxidative damage. On the other hand, the reverse transcriptase telomerase can add back telomeric repeats at the telomere ends. It has been suggested that once telomeres have reached a critical length, cells cease proliferation, also known as senescence. Evidence is accumulating that telomere shortening and subsequent senescence might play a crucial role in life-threatening diseases. So far, mathematical models described telomere shortening as an autonomous process, where the loss per cell division does not depend on the telomere length itself. In this study, published measurements of telomere distributions in human fibroblasts and human endothelial cells were used to show that telomeres shorten in a length-dependent fashion. Thereafter, a mathematical model of telomere attrition was composed, in which a shortening factor and an autonomous loss were incorporated. It was assumed that the percentage of senescence was related to the percentage of telomeres below a critical length. The model was compared with published data of telomere length and senescence of human endothelial cells using the maximum likelihood method. This enabled the estimation of physiologically important parameters and confirmed the length-dependency of telomere shortening. (C) 2004 Elsevier Ireland Ltd. All rights reserved.