Chiang Y Jeffrey, Nguyen My-Linh, Gurunathan Sujatha, Kaminker Patrick, Tessarollo Lino, Campisi Judith, Hodes Richard J
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Building 10, 4B36, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Mol Cell Biol. 2006 Mar;26(6):2037-43. doi: 10.1128/MCB.26.6.2037-2043.2006.
Telomere length and function are crucial factors that determine the capacity for cell proliferation and survival, mediate cellular senescence, and play a role in malignant transformation in eukaryotic systems. The telomere length of a specific mammalian species is maintained within a given range by the action of telomerase and telomere-associated proteins. TRF1 is a telomere-associated protein that inhibits telomere elongation by its binding to telomere repeats, preventing access to telomerase. Human TRF1 interacts with tankyrase 1 and tankyrase 2 proteins, two related members of the tankyrase family shown to have poly(ADP-ribose) polymerase activity. Human tankyrase 1 is reported to ADP-ribosylate TRF1 and to down-regulate the telomeric repeat binding activity of TRF1, resulting in telomerase-dependent telomere elongation. Human tankyrase 2 is proposed to have activity similar to that of tankyrase 1, although tankyrase 2 function has been less extensively characterized. In the present study, we have assessed the in vivo function of mouse tankyrase 2 by germ line gene inactivation and show that inactivation of tankyrase 2 does not result in detectable alteration in telomere length when monitored through multiple generations of breeding. This finding suggests that either mouse tankyrases 1 and 2 have redundant functions in telomere length maintenance or that mouse tankyrase 2 differs from human tankyrase 2 in its role in telomere length maintenance. Tankyrase 2 deficiency did result in a significant decrease in body weight sustained through at least the first year of life, most marked in male mice, suggesting that tankyrase 2 functions in potentially telomerase-independent pathways to affect overall development and/or metabolism.
端粒长度和功能是决定真核系统中细胞增殖和存活能力、介导细胞衰老以及在恶性转化中起作用的关键因素。特定哺乳动物物种的端粒长度通过端粒酶和端粒相关蛋白的作用维持在给定范围内。TRF1是一种端粒相关蛋白，它通过与端粒重复序列结合来抑制端粒延长，阻止端粒酶的接近。人类TRF1与端锚聚合酶1和端锚聚合酶2蛋白相互作用，端锚聚合酶家族的这两个相关成员显示具有聚（ADP-核糖）聚合酶活性。据报道，人类端锚聚合酶1会使TRF1发生ADP-核糖基化，并下调TRF1的端粒重复序列结合活性，从而导致端粒酶依赖性的端粒延长。尽管对端锚聚合酶2功能的表征较少，但有人提出人类端锚聚合酶2具有与端锚聚合酶1相似的活性。在本研究中，我们通过种系基因失活评估了小鼠端锚聚合酶2的体内功能，结果表明，在多代繁殖监测中，端锚聚合酶2的失活并未导致端粒长度出现可检测到的改变。这一发现表明，要么小鼠端锚聚合酶1和2在端粒长度维持中具有冗余功能，要么小鼠端锚聚合酶2在端粒长度维持中的作用与人类端锚聚合酶2不同。端锚聚合酶2缺陷确实导致体重显著下降，至少在生命的第一年持续存在，在雄性小鼠中最为明显，这表明端锚聚合酶2在可能不依赖端粒酶的途径中发挥作用，以影响整体发育和/或代谢。
