Telomere uncapping during in vitro T-lymphocyte senescence
Telomere uncapping during in vitro T-lymphocyte senescence
复制标题
DOI：
10.1111/j.1474-9726.2008.00448.x
复制
发表时间：
2009-02-01
期刊：
影响因子：
7.8
通讯作者：
Ffrench, Martine
中科院分区：
文献类型：
--
作者：
Chebel, Amel;Bauwens, Serge;Ffrench, Martine
正常的淋巴细胞代表了体细胞的例子，当受到刺激时能够诱导端粒酶活性。如前所述，我们发现，在淋巴细胞长期培养和反复刺激过程中，衰老细胞的出现与端粒缩短和端粒酶活性的进行性下降有关。我们进一步表明，这种缩短优先发生在长端粒，并中断在每个刺激的端粒长度的短暂增加。与端粒脱帽触发淋巴细胞衰老的事实一致，我们观察到γ-H2 AX和53 BP 1病灶以及端粒中表现出DNA损伤病灶的细胞百分比增加。这种DNA损伤反应可能与p16（ink 4a）在细胞刺激和细胞老化时的持续增加有关。值得注意的是，在每次刺激时，shelterin基因，如hTRF 1，hTANK 1，hTIN 2，hPOT 1和hRAP 1的表达降低。我们提出，端粒功能障碍在淋巴细胞衰老引起的反复刺激不仅是由于过度端粒缩短，但也从shelterin含量减少。这些观察结果可能与T细胞生物学和衰老有关。
Normal lymphocytes represent examples of somatic cells that are able to induce telomerase activity when stimulated. As previously reported, we showed that, during lymphocyte long-term culture and repeated stimulations, the appearance of senescent cells is associated with telomere shortening and a progressive drop in telomerase activity. We further showed that this shortening preferentially occured at long telomeres and was interrupted at each stimulation by a transitory increase in telomere length. In agreement with the fact that telomere uncapping triggers lymphocyte senescence, we observed an increase in gamma-H2AX and 53BP1 foci as well as in the percentage of cells exhibiting DNA damage foci in telomeres. Such a DNA damage response may be related to the continuous increase of p16(ink4a) upon cell stimulation and cell aging. Remarkably, at each stimulation, the expression of shelterin genes, such as hTRF1, hTANK1, hTIN2, hPOT1 and hRAP1, was decreased. We propose that telomere dysfunction during lymphocyte senescence caused by iterative stimulations does not only result from an excessive telomere shortening, but also from a decrease in shelterin content. These observations may be relevant for T-cell biology and aging.