BRCA1 Function in Post-Damage Nuclear Foci

BRCA1 在损伤后核病灶中的功能

• 批准号: 8080170
• 负责人: DAVID Morse LIVINGSTON
• 金额: $ 51.17万
• 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 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8080170
• 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. PUBLIC HEALTH RELEVANCE: BRCA1 is a breast and ovarian cancer gene. When it is inherited in a mutated state, women experience a much higher than normal risk of developing one or both of these diseases. This proposal is aimed at understanding how BRCA1 functions inside the nucleus of cells and why, when its function is rendered defective by mutation, cancer cells develop.

描述（由申请人提供）：BRCA1是一种肿瘤抑制基因产物，致力于抑制乳腺癌和卵巢癌的发展。它编码 ​​1863 个残基的核蛋白 p220。 p220 对多种形式的基因组完整性控制做出了贡献，其中包括支持通过同源重组 (HR) 修复双链 DNA 断裂 (DSB) 的能力。许多间接证据表明p220支持HR的能力和执行其肿瘤抑制功能之间存在很强的相关性，但两者在生化方面如何联系尚不清楚。更具体地说，p220 必须执行哪些体内生化功能才能发挥其肿瘤抑制功能以及这两组功能如何相互联系也是未知的。在这方面，在 DSB 产生后（例如通过电离辐射），p220 迅速被吸引到这些受损位点，一段时间后，集中在这些位置形成的焦点核结构（又名电离辐射诱导焦点 = IRIF）中。 p220 一旦集中在 IRIF 中，会发挥什么功能，以及它们如何（正如所怀疑的那样）有助于肿瘤抑制，这也是未知的。最近，我们和其他人检测到一系列特定的生化步骤，使 p220 能够访问 IRIF。它们涉及核多聚泛素结合蛋白 Rap80、其相关的去泛素酶 BRCC36 和 Abraxas（一种充当 p220 和 Rap80 之间桥梁的核蛋白）的活性。全部集中在 IRIF 中并参与共浓缩 p220。该提案的目的是： a) 破译将 Rap80 与 IRIF 联系在一起的特定生化事件； b) 了解与 IRIF 中 p220 浓度相关的功能意义； c) 了解这些事件以何种方式与 p220 癌症抑制功能的执行相关。公共健康相关性：BRCA1 是一种乳腺癌和卵巢癌基因。当它以突变状态遗传时，女性患其中一种或两种疾病的风险比正常情况高得多。该提案旨在了解 BRCA1 在细胞核内如何发挥作用，以及为什么当其功能因突变而出现缺陷时，癌细胞就会形成。