The Connection Between Cell Fate and Telomere
The Connection Between Cell Fate and Telomere
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DOI：
10.1007/978-3-030-49844-3_3
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发表时间：
2021-01-01
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影响因子：
--
通讯作者：
Engin, Atilla
中科院分区：
文献类型：
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作者：
Engin, Ayse Basak;Engin, Atilla
端粒酶活性的消除会导致端粒缩短，这一过程最终会破坏染色体末端的稳定性，导致基因组不稳定和细胞生长停滞或死亡。端粒缩短导致达到“海弗利克极限”，并使细胞过渡到衰老状态。如果绕过衰老，细胞就会因检查点缺失而陷入危机。这一过程导致大量细胞死亡，并伴随着端粒进一步缩短和自发端粒融合。在哺乳动物细胞的功能性端粒中，DNA 含有 TTAGGG 双链串联重复序列。 Shelterin 复合物由六种不同的蛋白质组成，是调节细胞端粒长度和稳定性所必需的。端粒重复结合蛋白 2 (TRF2) 的端粒保护依赖于通过形成 T 环结构来抑制 DNA 损伤反应 (DDR)。许多蛋白激酶有助于 DDR 激活细胞周期检查点途径，并阻止 DNA 复制，直到受损的 DNA 得到修复。因此，细胞命运和端粒长度相关的端粒酶活性之间的联系受到多种蛋白激酶活性的调节。相反，衰老细胞中 DNA 损伤检查点蛋白激酶的失活可以使细胞周期进程恢复到 S 期。因此，端粒引发的衰老是一种 DNA 损伤检查点反应，由功能失调的端粒直接激活。在这篇综述中，除了上述内容外，还讨论了主要修复途径的选择，包括端粒脱帽端粒功能障碍中的非同源末端连接和同源重组。
Abolition of telomerase activity results in telomere shortening, a process that eventually destabilizes the ends of chromosomes, leading to genomic instability and cell growth arrest or death. Telomere shortening leads to the attainment of the "Hayflick limit", and the transition of cells to state of senescence. If senescence is bypassed, cells undergo crisis through loss of checkpoints. This process causes massive cell death concomitant with further telomere shortening and spontaneous telomere fusions. In functional telomere of mammalian cells, DNA contains double--stranded tandem repeats of TTAGGG. The Shelterin complex, which is composed of six different proteins, is required for the regulation of telomere length and stability in cells. Telomere protection by telomeric repeat binding protein 2 (TRF2) is dependent on DNA damage response (DDR) inhibition via formation of T-loop structures. Many protein kinases contribute to the DDR activated cell cycle checkpoint pathways, and prevent DNA replication until damaged DNA is repaired. Thereby, the connection between cell fate and telomere length- associated telomerase activity is regulated by multiple protein kinase activities. Contrarily, inactivation of DNA damage checkpoint protein kinases in senescent cells can restore cell- cycle progression into S phase. Therefore, telomere-initiated senescence is a DNA damage checkpoint response that is activated with a direct contribution from dysfunctional telomeres. In this review, in addition to the above mentioned, the choice of main repair pathways, which comprise non-homologous end joining and homologous recombination in telomere uncapping telomere dysfunctions, are discussed.