Karlseder J, Broccoli D, Dai Y, Hardy S, de Lange T
Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, NY 10021, USA. Cell Genesys, Foster City, CA 94405, USA.
Science. 1999 Feb 26;283(5406):1321-5. doi: 10.1126/science.283.5406.1321.
Although broken chromosomes can induce apoptosis, natural chromosome ends (telomeres) do not trigger this response. It is shown that this suppression of apoptosis involves the telomeric-repeat binding factor 2 (TRF2). Inhibition of TRF2 resulted in apoptosis in a subset of mammalian cell types. The response was mediated by p53 and the ATM (ataxia telangiectasia mutated) kinase, consistent with activation of a DNA damage checkpoint. Apoptosis was not due to rupture of dicentric chromosomes formed by end-to-end fusion, indicating that telomeres lacking TRF2 directly signal apoptosis, possibly because they resemble damaged DNA. Thus, in some cells, telomere shortening may signal cell death rather than senescence.
尽管断裂的染色体会诱导细胞凋亡，但天然染色体末端（端粒）不会引发这种反应。研究表明，这种对细胞凋亡的抑制涉及端粒重复序列结合因子2（TRF2）。抑制TRF2会导致一部分哺乳动物细胞类型发生凋亡。这种反应由p53和ATM（共济失调毛细血管扩张症突变）激酶介导，这与DNA损伤检查点的激活一致。细胞凋亡并非由于端对端融合形成的双着丝粒染色体断裂所致，这表明缺乏TRF2的端粒直接发出细胞凋亡信号，可能是因为它们类似于受损的DNA。因此，在某些细胞中，端粒缩短可能预示细胞死亡而非衰老。
