Greenberg R A
Department of Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.
Curr Mol Med. 2005 Mar;5(2):213-8. doi: 10.2174/1566524053586590.
Eukaryotic chromosomes terminate in specialized nucleic acid-protein complexes known as telomeres. Disruption of telomere structure by erosion of telomeric DNA or loss of telomere binding protein function activates a signal transduction program that closely resembles the cellular responses generated upon DNA damage. Telomere dysfunction in turn induces a permanent proliferation arrest known as senescence. Senescence is postulated to perform a tumor suppressor function by limiting cellular proliferative capacity, thus imposing a barrier to cellular immortalization. Genetic or epigenetic silencing of components of the DNA damage pathway, allows cells to proliferate beyond senescence limits. However, these cells eventually reach a stage of extreme telomere dysfunction known as crisis that is characterized by cell death and the concomitant appearance of cytogenetic abnormalities. Telomeric crisis produces significant chromosomal instability, a hallmark of human cancer, and may thus be relevant to carcinogenesis by increasing the occurrence of genetic alterations that would favor neoplastic transformation. The following review examines the relationship of telomere function during crisis in accelerating chromosomal instability and cancer.
真核生物染色体末端是由称为端粒的特殊核酸 - 蛋白质复合物构成。端粒DNA的侵蚀或端粒结合蛋白功能的丧失导致端粒结构破坏，从而激活一个信号转导程序，该程序与DNA损伤时产生的细胞反应极为相似。端粒功能障碍进而诱导一种称为衰老的永久性增殖停滞。据推测，衰老通过限制细胞增殖能力发挥肿瘤抑制功能，从而对细胞永生化形成障碍。DNA损伤途径成分的基因或表观遗传沉默使细胞能够增殖超越衰老极限。然而，这些细胞最终会进入一个极端端粒功能障碍的阶段，即危机，其特征是细胞死亡以及伴随出现的细胞遗传学异常。端粒危机产生显著的染色体不稳定性，这是人类癌症的一个标志，因此可能通过增加有利于肿瘤转化的基因改变的发生率而与致癌作用相关。以下综述探讨了危机期间端粒功能在加速染色体不稳定和癌症方面的关系。
