BRCA1 Function in Post-Damage Nuclear Foci

BRCA1 在损伤后核病灶中的功能

• 批准号: 8465745
• 负责人: DAVID Morse LIVINGSTON
• 金额: $ 48.08万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8465745
• 关键词: BRCA1 gene; Binding; Binding Proteins; Biochemical; Breast; Cell Nucleus; Complex; DNA Double Strand Break; Development; Disease; Double Strand Break Repair; Event; Generations; Genome; Inherited; Ionizing radiation; Learning; Location; Malignant Neoplasms; Malignant neoplasm of ovary; Mutate; Mutation; Nuclear; Nuclear Protein; Nuclear Structure; Oncogenes; Polyubiquitin; Process; Proteins; Risk; Series; Site; Structure; Time; Tumor Suppression; Tumor Suppressor Genes; Woman; Y protein; cancer cell; clinically relevant; experience; homologous recombination; in vivo; insight; malignant breast neoplasm; public health relevance; repaired; response; tumor; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): BRCA1 is a tumor suppressor gene product dedicated to the suppression of breast and ovarian cancer development. It encodes an 1863 residue nuclear protein, p220. p220 makes contributions to multiple forms of genome integrity control, among which is an ability to support the repair of double strand DNA breaks (DSB) by homologous recombination (HR). Much circumstantial evidence suggests a strong correlation between the ability of p220 to support HR and to perform its tumor suppression function, but how the two are connected, biochemically, is unknown. More specifically, what in vivo biochemical functions p220 must execute to perform its tumor suppressing function and how the two sets of functions are connected to one another are also unknown. In this regard, after the generation of DSBs (e.g. by ionizing radiation), p220 is rapidly attracted to these damaged sites and, some time later, concentrates in focal nuclear structures (aka Ionizing Radiation Induced Foci=IRIF) that form at these locations. What functions p220 performs, once concentrated in IRIF, and how, as is suspected, they contribute to tumor suppression are also unknown. Recently, we and others detected a series of specific biochemical steps that allow p220 to gain access to IRIF. They involve the activities of a nuclear, polyubiquitin-binding protein, Rap80, its associated deubiquitinase, BRCC36, and Abraxas, a nuclear protein that serves as a bridge between p220 and Rap80. All concentrate in IRIF and participate in co-concentrating p220. This proposal is aimed at: a) deciphering the specific biochemical events that tether Rap80 to IRIF; b) at understanding the functional significance associated with p220 concentration in IRIF; and c) learning in what ways these events relate to the execution of p220 cancer suppression function.

描述（由申请人提供）：BRCA1是一种致力于抑制乳腺癌和卵巢癌发育的肿瘤抑制基因产物。它编码1863年的残基核蛋白，P220。 P220对多种形式的基因组完整性控制作出了贡献，其中包括通过同源重组（HR）支持双链DNA断裂（DSB）的能力。许多间接证据表明，p220支持人力资源并执行其肿瘤抑制功能之间的能力有很强的相关性，但是两者在生化上是如何连接的。更具体地说，在体内生化功能P220必须执行其抑制肿瘤功能以及两组功能如何相互连接也未知。在这方面，在生成DSB（例如，通过电离辐射）生成后，P220迅速吸引到这些受损的位点，一段时间后，浓缩的浓度是在这些位置形成的焦点核结构（又称电离辐射诱导的灶）。什么功能P220曾经集中在IRIF中，以及如何应对肿瘤抑制作用，这也未知。最近，我们和其他人发现了一系列特定的生化步骤，使P220可以访问IRIF。它们涉及核，多泛素结合蛋白，RAP80，其相关的去泛素酶，BRCC36和Abraxas的活性，该蛋白是P220和RAP80之间的桥梁。所有人都集中在IRIF中，并参与共浓缩P220。该提议的目的是：a）破译将Rap80绑定到IRIF的特定生化事件； b）了解与IRIF中P220浓度相关的功能意义； c）学习这些事件与p220癌症抑制功能的执行有关。