Dipartimento di Biotecnologie e Bioscienze, Università degli Studi di Milano-Bicocca, 20126 Milano, Italy.
Cells. 2022 Oct 14;11(20):3224. doi: 10.3390/cells11203224.
Early work by Muller and McClintock discovered that the physical ends of linear chromosomes, named telomeres, possess an inherent ability to escape unwarranted fusions. Since then, extensive research has shown that this special feature relies on specialized proteins and structural properties that confer identity to the chromosome ends, thus allowing cells to distinguish them from intrachromosomal DNA double-strand breaks. Due to the inability of conventional DNA replication to fully replicate the chromosome ends and the downregulation of telomerase in most somatic human tissues, telomeres shorten as cells divide and lose this protective capacity. Telomere attrition causes the activation of the DNA damage checkpoint that leads to a cell-cycle arrest and the entering of cells into a nondividing state, called replicative senescence, that acts as a barrier against tumorigenesis. However, downregulation of the checkpoint overcomes this barrier and leads to further genomic instability that, if coupled with re-stabilization of telomeres, can drive tumorigenesis. This review focuses on the key experiments that have been performed in the model organism to uncover the mechanisms that protect the chromosome ends from eliciting a DNA damage response, the conservation of these pathways in mammals, as well as the consequences of their loss in human cancer.
早期由 Muller 和 McClintock 进行的工作发现，线性染色体的物理末端，称为端粒，具有逃避不必要融合的固有能力。从那时起，广泛的研究表明，这种特殊特征依赖于专门的蛋白质和结构特性，赋予染色体末端身份，从而允许细胞将它们与染色体内部的 DNA 双链断裂区分开来。由于传统的 DNA 复制无法完全复制染色体末端，并且大多数体细胞组织中的端粒酶下调，因此随着细胞分裂，端粒会缩短并失去这种保护能力。端粒损耗会激活 DNA 损伤检查点，导致细胞周期停滞并进入非分裂状态，称为复制性衰老，这是防止肿瘤发生的障碍。然而，检查点的下调克服了这一障碍，并导致进一步的基因组不稳定性，如果与端粒的重新稳定相结合，可能会导致肿瘤发生。这篇综述重点介绍了在模型生物中进行的关键实验，以揭示保护染色体末端免受 DNA 损伤反应的机制，这些途径在哺乳动物中的保守性，以及它们在人类癌症中的丧失所带来的后果。
