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Conserved modes of recruitment of ATM, ATR and DNA-PKcs to sites of DNA damage

机译：将ATM，ATR和DNA-PKcs募集到DNA损伤部位的保守模式

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摘要

Ataxia-telangiectasia mutated (ATM), ataxia-telangiectasia and Rad3-related (ATR) and DNA-dependent protein kinase catalytic subunit (DNA-PKcs) are members of the phosphoinositide-3-kinase-related protein kinase (PIKK) family, and are rapidly activated in response to DNA damage. ATM and DNA-PKcs respond mainly to DNA double-strand breaks, whereas ATR is activated by single-stranded DNA and stalled DNA replication forks. In all cases, activation involves their recruitment to the sites of damage. Here we identify related, conserved carboxy-terminal motifs in human Nbs1, ATRIP and Ku80 proteins that are required for their interaction with ATM, ATR and DNA-PKcs, respectively. These motifs are essential not only for efficient recruitment of ATM, ATR and DNA-PKcs to sites of damage, but are also critical for ATM-, ATR- and DNA-PKcs-mediated signalling events that trigger cell cycle checkpoints and DNA repair. Our findings reveal that recruitment of these PIKKs to DNA lesions occurs by common mechanisms through an evolutionarily conserved motif, and provide direct evidence that PIKK recruitment is required for PIKK-dependent DNA-damage signalling.
机译：共济失调-毛细血管扩张（ATM），共济失调-毛细血管扩张和Rad3相关（ATR）和DNA依赖性蛋白激酶催化亚基（DNA-PKcs）是磷酸肌醇3-激酶相关蛋白激酶（PIKK）家族的成员，并且响应DNA损伤而被迅速激活。 ATM和DNA-PKcs主要对DNA双链断裂作出反应，而ATR由单链DNA和停滞的DNA复制叉激活。在所有情况下，激活都涉及将它们招募到受损地点。在这里，我们确定了人类Nbs1，ATRIP和Ku80蛋白中相关的，保守的羧基末端基序，它们分别是它们与ATM，ATR和DNA-PKcs相互作用所必需的。这些基序不仅对于有效地将ATM，ATR和DNA-PKcs募集到损伤部位至关重要，而且对于触发ATM，ATR和DNA-PKcs介导的触发细胞周期检查点和DNA修复的信号转导事件也至关重要。我们的发现表明，这些PIKK募集到DNA损伤的过程是通过进化上保守的基序通过常见的机制发生的，并提供了直接证据表明PIKK募集是DNA依赖性DNA损伤信号传导所必需的。

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  • 来源
    《Nature》 |2005年第7033期|p.605-611|共7页
  • 作者

    Jacob Falck; Julia Coates; Stephen P. Jackson;

  • 作者单位

    The Wellcome Trust and Cancer Research UK Gurdon Institute, and Department of Zoology, Cambridge University, Tennis Court Road, Cambridge CB2 1QN, UK;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 自然科学总论;
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