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Ku is a 5-dRP/AP lyase that excises nucleotide damage near broken ends

机译：Ku是一种5-dRP / AP裂解酶，可消除断裂末端附近的核苷酸损伤

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摘要

Mammalian cells require non-homologous end joining (NHEJ) for the efficient repair of chromosomal DNA double-strand breaks. A key feature of biological sources of strand breaks is associated nucleotide damage, including base loss (abasic or apurinic/ apyrimidinic (AP) sites). At single-strand breaks, 5'-terminal abasic sites are' excised by the 5'-deoxyribose-5-phosphate (5'-dRP) lyase activity of DNA polymerase β (pol β): here we show, in vitro and in cells, that accurate and efficient repair by NHEJ of double-strand breaks with such damage similarly requires 5'-dRP/AP lyase activity. Classically defined NHEJ is moreover uniquely effective at coupling this end-cleaning step to joining in cells, helping to distinguish this pathway from otherwise robust alternative NHEJ pathways. The NHEJ factor Ku can be identified as an effective 5'-dRP/AP lyase. In a similar manner to other lyases, Ku nicks DNA 3' of an abasic site by a mechanism involving a Schiff-base covalent intermediate with the abasic site. We show by using cell extracts that Ku is essential for the efficient removal of AP sites near double-strand breaks and, consistent with this result, that joining of such breaks is specifically decreased in cells complemented with a lyase-attenuated Ku mutant. Ku had previously been presumed only to recognize ends and recruit other factors that process ends; our data support an unexpected direct role for Ku in end-processing steps as well.
机译：哺乳动物细胞需要非同源末端连接（NHEJ）才能有效修复染色体DNA双链断裂。链断裂的生物学来源的关键特征是相关的核苷酸损伤，包括碱基丢失（基本或嘌呤/嘧啶（AP）位点）。在单链断裂处，DNA聚合酶β（polβ）的5'-脱氧核糖-5-磷酸（5'-dRP）裂解酶活性切除了5'-末端无碱基位点： NHEJ准确有效地修复这种损伤的双链断裂细胞，同样需要5'-dRP / AP裂解酶活性。此外，经典定义的NHEJ在将这一最终清洁步骤与细胞连接耦合方面具有独特的功效，有助于将该途径与其他健壮的NHEJ替代途径区分开。 NHEJ因子Ku可被鉴定为有效的5'-dRP / AP裂解酶。以与其他裂解酶类似的方式，Ku通过一种涉及席夫碱共价中间物与无碱基位点的机理在无碱基位点的DNA 3'上形成缺口。我们显示通过使用细胞提取物，Ku对于有效去除双链断裂附近的AP位点是必不可少的，并且与该结果一致，在含有裂解酶减毒的Ku突变体补充的细胞中，这种断裂的连接特别地减少了。以前，Ku仅被认为仅识别目的并吸收其他过程结束的因素。我们的数据也支持Ku在最终处理步骤中出乎意料的直接作用。

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  • 来源
    《Nature》 |2010年第7292期|p.1214-1217|共4页
  • 作者

    Steven A. Roberts; Natasha Strande; Martin D. Burkhalter; Christina Strom; Jody M. Havener; Paul Hasty; Dale A. Ramsden;

  • 作者单位

    Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, and Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

    Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, and Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

    Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, and Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

    Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, and Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

    Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, and Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA;

    Department of Molecular Medicine and Institute of Biotechnology, The University of Texas Health Science Center at San Antonio, 15355 Lambda Drive, San Antonio, Texas 78245, USA;

    Department of Biochemistry and Biophysics, Lineberger Comprehensive Cancer Center, and Curriculum in Genetics and Molecular Biology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, 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);
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