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首页> 外文期刊>Nature >Saccharomyces cerevisiae ATM orthologue suppresses break-induced chromosome translocations
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Saccharomyces cerevisiae ATM orthologue suppresses break-induced chromosome translocations

机译：酿酒酵母ATM直向同源物抑制断裂诱导的染色体易位

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摘要

Chromosome translocations are frequently associated with many types of blood-related cancers and childhood sarcomas. Detection of chromosome translocations assists in diagnosis, treatment and prognosis of these diseases; however, despite their importance to such diseases, the molecular mechanisms leading to chromosome translocations are not well understood. The available evidence indicates a role for non-homologous end joining (NHEJ) of DNA double-strand breaks (DSBs) in their origin. Here we develop a yeast-based system that induces a reciprocal chromosome trans-location by formation and ligation of breaks on two different chromosomes. We show that interchromosomal end joining is efficiently suppressed by the Tell- and Mrell-Rad50-Xrs2-dependent pathway; this is distinct from the role of Tell in telo-meric integrity and from Mecl- and Tell-dependent checkpoint controls. Suppression of DSB-induced chromosome translocations depends on the kinase activity of Tell and Dunl, and the damage-induced phosphorylation of Sae2 and histone H2AX proteins. Tell- and Sae2-dependent tethering and promotion of 5' to 3' degradation of broken chromosome ends discourage error-prone NHEJ and interchromosomal NHEJ, preserving chromosome integrity on DNA damage. Our results indicate that, like human ATM, Tell serves as a key regulator for chromosome integrity in the pathway that reduces the risk for DSB-induced chromosome translocations, and are probably pertinent to the oncogenic chromosome translocations in ATM-deficient cells.
机译：染色体易位经常与许多类型的血液相关癌症和儿童肉瘤相关。染色体易位的检测有助于这些疾病的诊断，治疗和预后；然而，尽管它们对此类疾病很重要，但导致染色体易位的分子机制仍未得到很好的了解。现有证据表明DNA双链断裂（DSB）起源的非同源末端连接（NHEJ）发挥了作用。在这里，我们开发了一种基于酵母的系统，该系统通过在两个不同染色体上形成和连接断裂来诱导相互的染色体易位。我们表明，Tell-和Mrell-Rad50-Xrs2依赖性途径可有效抑制染色体间末端连接。这与Tell在端粒完整性中的作用以及Mecl和Tell依赖的检查点控件不同。 DSB诱导的染色体易位的抑制取决于Tell和Dunl的激酶活性，以及​​损伤诱导的Sae2和组蛋白H2AX蛋白的磷酸化。依赖于Tell和Sae2的系链，并促进断裂的染色体末端从5'到3'的降解，阻止了容易出错的NHEJ和染色体间NHEJ，从而保留了DNA损伤时的染色体完整性。我们的结果表明，与人的ATM一样，Tell在降低染色体中DSB诱导的染色体易位风险的途径中充当染色体完整性的关键调节剂，并且可能与ATM缺陷细胞中的致癌染色体易位有关。

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  • 来源
    《Nature》 |2008年第7203期|p.543-546|共4页
  • 作者

    Kihoon Lee; Yu Zhang; Sang Eun Lee;

  • 作者单位

    Department of Molecular Medicine and Institute of Biotechnology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78245, USA;

  • 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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