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首页> 外文学位 >DNA end protection at double strand breaks and telomeres by Ku70/80 and Cdc13.
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DNA end protection at double strand breaks and telomeres by Ku70/80 and Cdc13.

机译：Ku70 / 80和Cdc13在双链断裂和端粒的DNA末端保护。

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摘要

Non-homologous end joining (NHEJ) and homologous recombination (HR) are the two primary pathways for the repair of DNA double strand breaks. The choice between the two pathways is a highly regulated process dependent on cell cycle stage and DNA damage type. HR is initiated via extensive resection of the double strand DNA break ends to produce long single-stranded DNA overhangs, which are then coated by the ssDNA binding protein RPA. This resection cements the decision for pathway choice toward HR. As the driver of NHEJ, the Ku70/80 heterodimer plays a role in antagonizing this resection. Ku70/80 has been implicated in blocking Exol-mediated DNA end digestion both in vivo and in vitro. In this thesis, I investigate the effect of various DNA end structures on Ku70/80 loading and protection functions. I find that Ku70/80 can efficiently load onto dsDNA ends with an appended ssDNA region, where it localizes to the ss-dsDNA junction and protects the 5' strand from digestion. A DNA-binding deficient mutant of the protein, however, is unable to block Exo1. RPA presence at moderate length overhangs, but not those of longer lengths, Ku's protection capabilities against Exol. This suggests a model in which DNA overhang length affects the equilibrium between Ku and RPA at DNA ends containing ssDNA regions, which in turn influences the progression of DNA end resection. Apart from regulation of Exo1 at DNA double-strand breaks, Ku70/80 has also been implicated in its regulation at telomeres. Telomeres are the nucleoprotein complex assembled at the extremities of linear chromosomes. Their structure harbors a DNA double stranded break with a 3' single-stranded region, and is protected from extensive resection by the associated proteins. The formation of this overhang is dependent on the activity of resection factors also involved in homologous recombination. DNA capping factors are present on telomere ends to regulate their formation and maintenance. Ku70/80 and Cdc13-Stn1-Ten1 are two such complexes with roles in protecting telomeric DNA ends from resection. In the latter half of this work, I demonstrate that Ku70/80 and Cdc13 are able to protect the telomeric ends from resection by Exo l . Furthermore, Cdc 13 competition with RPA for binding to ssDNA overhangs is highly influenced by overhang length and presence of Stn1 and Ten1, suggesting an intricate mechanism for telomeric length maintenance.
机译：非同源末端连接（NHEJ）和同源重组（HR）是修复DNA双链断裂的两个主要途径。两种途径之间的选择是取决于细胞周期阶段和DNA损伤类型的高度调控的过程。 HR是通过广泛切除双链DNA断裂末端而产生的，以产生长的单链DNA突出端，然后被ssDNA结合蛋白RPA覆盖。该切除术巩固了通往HR的途径选择的决定。作为NHEJ的驱动程序，Ku70 / 80异二聚体在对抗这种切除中起着重要作用。 Ku70 / 80与体内和体外阻断Exol介导的DNA末端消化有关。在本文中，我研究了各种DNA末端结构对Ku70 / 80负载和保护功能的影响。我发现Ku70 / 80可以有效地加载到带有附加ssDNA区域的dsDNA末端，该区域定位于ss-dsDNA连接处并保护5'链免于消化。但是，该蛋白质的DNA结合缺陷型突变体无法阻断Exo1。 RPA具有中等长度的悬垂，但不具有较长的悬垂，这是Ku对Exol的防护能力。这表明了一种模型，其中DNA突出端长度影响包含ssDNA区域的DNA末端的Ku和RPA之间的平衡，进而影响DNA末端切除的进程。除了在DNA双链断裂处调控Exo1外，Ku70 / 80还涉及其在端粒的调控。端粒是在线性染色体末端组装的核蛋白复合物。它们的结构带有一个带有3'单链区域的DNA双链断裂，并受到相关蛋白质的保护，免受广泛切除。该突出端的形成取决于也参与同源重组的切除因子的活性。 DNA封端因子存在于端粒末端，以调节其形成和维持。 Ku70 / 80和Cdc13-Stn1-Ten1是两个这样的复合物，在保护端粒DNA末端不被切除中起作用。在本文的后半部分，我证明了Ku70 / 80和Cdc13能够保护端粒末端免受Exo 1切除。此外，Cdc 13与RPA竞争与ssDNA突出端的结合在很大程度上受到突出端长度以及Stn1和Ten1的存在的影响，这暗示了端粒长度维持的复杂机制。

著录项

  • 作者

    Krasner, Danielle Sonya.;

  • 作者单位

    Yale University.;

  • 授予单位 Yale University.;
  • 学科 Biochemistry.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 263 p.
  • 总页数 263
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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