Resolution of Complex Breaks by Nonhomologous End Joining

通过非同源末端连接解决复杂断裂

• 批准号: 8818171
• 负责人: DALE A RAMSDEN
• 金额: $ 28.62万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-01-04 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8818171
• 关键词: APTX gene; Active Sites; Address; Aging; Anthracyclines; Bypass; Cells; Chromosomal Breaks; Chromosomes; Complex; DNA-PKcs; Effectiveness; Employment; Enzymes; Genetic Polymorphism; Genome Stability; Human; Immune; Immunoglobulin Class Switching; Immunoglobulin Switch Recombination; Investigation; Ionizing radiation; Left; Ligase; Ligation; Lyase; Mammals; Medical; Methods; Modeling; Nature; Neuraxis; Nucleotides; Pathway interactions; Poison; Proteins; Radiation; Repair Complex; Resolution; Role; Safety; Shapes; Site; Structure; Topoisomerase; Topoisomerase II; Tyrosine; Validation; Variant; Work; XRCC4 gene; adduct; adenylate; artemis; base; cancer radiation therapy; cancer therapy; carcinogenesis; chemotherapy; coping; design; endonuclease; fitness; improved; inhibitor/antagonist; inorganic phosphate; insight; killings; neoplastic cell; nervous system development; nuclease; public health relevance; repaired; research study; tumor; tumor progression

DESCRIPTION (provided by applicant): Nonhomologous end joining (NHEJ) is a major pathway for resolving chromosome double strand breaks. We have determined NHEJ's pivotal role in maintaining genome stability is at least in part due to a unique ability to cope with the complex broken end structures expected. We will address here if this is because NHEJ is adaptive - if it can sense differences in the type of damage, and tailor its path to resolution accordingly. In Aim 1 we will address possible mechanisms for its unique ability to "bypass" the more subtle classes of damage at ends. In Aim 2 we will address the role of three enzymes that are highly specific for removing different types of damage from ends. We will determine how "end cleaning" enzymes help define a next line of defense, to aid in resolving damaged ends when the damage cannot be bypassed. In Aim 3 we will investigate the role of Artemis, a nuclease, which also removes damage from ends but which does not appear to be specific for a given type of damage. We will determine if Artemis defines the last line of defense, and helps remove damage at ends that could neither be bypassed nor "cleaned". The effectiveness of some cancer therapies - radiation and certain chemotherapy agents - relies to a great degree on their ability to generate complex end structures that interfere with repair by NHEJ. Our studies will clarify the mechanism of resolving these ends, and how the mechanism can be manipulated to make therapies more effective and safer.

描述（由申请人提供）：非同源末端连接（NHEJ）是解决染色体双链断裂的主要途径。我们已经确定了NHEJ在维持基因组稳定性中的关键作用，至少部分是由于应对预期的复杂破裂端结构的独特能力。如果这是因为NHEJ是自适应的，我们将在这里解决 - 如果它可以感觉到损害类型的差异，并相应地量身定制其解决方案。在AIM 1中，我们将解决其独特能力的可能机制，以“绕过”末端的更微妙的损害类别。在AIM 2中，我们将解决三种酶的作用，这些酶对于去除两端的不同类型的损害而高度特定。我们将确定“结束清洁”酶如何帮助定义下一条防线，以帮助在无法绕过损坏时解决损坏的终点。在AIM 3中，我们将研究Artemis（一种核酸酶）的作用，该核酸酶也可以消除末端的损害，但似乎并非特定于给定类型的损害。我们将确定Artemis是否定义了最后的防线，并有助于消除既不会被绕过也不会“清洁”的末端损坏。某些癌症疗法的有效性 - 放射线和某些化学疗法 - 在很大程度上取决于它们产生复杂的终端结构的能力，从而干扰NHEJ的维修。我们的研究将阐明解决这些目的的机制，以及如何操纵该机制以使疗法更有效和更安全。