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Telomere biology: integrating chromosomal end protection with DNA damage response

机译：端粒生物学：将染色体末端保护与DNA损伤反应整合在一起

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Telomeres play the key protective role at chromosomes. Many studies indicate that loss of telomere function causes activation of DNA damage response. Here, we review evidence supporting interdependence between telomere maintenance and DNA damage response and present a model in which these two pathways are combined into a single mechanism for protecting chromosomal integrity. Proteins directly involved in telomere maintenance and DNA damage response include Ku, DNA-PKcs, RAD51D, PARP-2, WRN and RAD50/MRE11/NBS1 complex. Since most of these proteins participate in the repair of DNA double-strand breaks (DSBs), this was perceived by many authors as a paradox, given that telomeres function to conceal natural DNA ends from mechanisms that detect and repair DSBs. However, we argue here that the key function of one particular DSB protein, Ku, is to prevent or control access of telomerase, the enzyme that synthesises telomeric sequences, to both internal DSBs and natural chromosomal ends. This view is supported by observations that Ku has a high affinity for DNA ends; it acts as a negative regulator of telomerase and that telomerase itself can target internal DSBs. Ku then directs other DSB repair/telomere maintenance proteins to either repair DSBs at internal chromosomal sites or prevent uncontrolled elongation of telomeres by telomerase. This model eliminates the above paradox and provides a testable scenario in which the role of DSB repair proteins is to protect chromosomal integrity by balancing repair activities and telomere maintenance. In our model, a close association between telomeres and different DNA damage response factors is not an unexpected event, but rather a logical result of chromosomal integrity maintenance activities.
机译：端粒在染色体上起着关键的保护作用。许多研究表明端粒功能的丧失会引起DNA损伤反应的激活。在这里，我们审查了支持端粒维持和DNA损伤反应之间相互依赖的证据，并提出了一个模型，其中将这两种途径组合为保护染色体完整性的单一机制。直接参与端粒维持和DNA损伤反应的蛋白质包括Ku，DNA-PKcs，RAD51D，PARP-2，WRN和RAD50 / MRE11 / NBS1复合物。由于这些蛋白质大多数都参与DNA双链断裂（DSB）的修复，因此许多研究者认为这是一个悖论，因为端粒的作用是从检测和修复DSB的机制中隐藏天然的DNA末端。但是，我们在这里认为，一种特定的DSB蛋白Ku的关键功能是阻止或控制端粒酶（一种合成端粒序列的酶）同时进入内部DSB和天然染色体末端。 Ku的DNA末端具有很高的亲和力，这一观点得到了支持。它充当端粒酶的负调节剂，并且端粒酶本身可以靶向内部DSB。然后，Ku指导其他DSB修复/端粒维持蛋白在内部染色体位点修复DSB或防止端粒酶控制端粒的不受控制的伸长。该模型消除了上述矛盾，并提供了一种可测试的方案，其中DSB修复蛋白的作用是通过平衡修复活性和端粒维护来保护染色体完整性。在我们的模型中，端粒和不同的DNA损伤反应因子之间的紧密联系不是意外事件，而是染色体完整性维持活动的逻辑结果。

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  • 来源
    《Chromosoma》 |2005年第4期|275-285|共11页
  • 作者

    Predrag Slijepcevic; Suliman Al-Wahiby;

  • 作者单位

    Brunel Institute of Cancer Genetics and Pharmacogenomics Division of Biosciences School of Health Sciences and Social Care Brunel University Uxbridge Middlesex UB8 3PH UK;

    Brunel Institute of Cancer Genetics and Pharmacogenomics Division of Biosciences School of Health Sciences and Social Care Brunel University Uxbridge Middlesex UB8 3PH UK;

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