Targeting the function of BRCA1 in the DNA damage response network.

靶向 DNA 损伤反应网络中 BRCA1 的功能。

• 批准号: 2879783
• 金额: --
• 依托单位: University of Leeds
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2879783
• 关键词: Targeting; function; BRCA1; DNA; damage

Breast cancer type 1 susceptibility (BRCA1) protein is a protein encoded by the tumour suppressor gene of the same name, BRCA1. Although involved in several cellular processes such as apoptosis, activation of cell-cycle check points, ubiquitination and transcription regulation, this project will primarily focus on the role of BRCA1 in DNA damage response (DDR). The BRCA1 protein possesses a tandem repeat of the functional domain, BRCA1 C-terminus domain (BRCT). The BRCT domains of BRCA1 are of particular interest as the structural arrangement of the protein forms a cleft, enabling a binding pocket for phosphorylated serine on the N-terminal repeat and a hydrophobic pocket for binding phenylalanine on the C-terminal repeat. Capacity to bind with phosphorylated protein partners containing a pSPxF motif is necessary for BRCA1 to fulfil its role in DNA repair and tumour suppression. To investigate the mechanisms of these protein-protein interactions and probe the function of BRCA1 in the cellular environment, this project will utilise a collection of Affimer proteins as binding partners for wild type and mutant forms of BRCA1. The development of a workflow that can elucidate the DDR mechanisms of BRCA1 could be applied to other proteins with BRCT domains in order to understand the broader biological significance of these domains in DDR, tumour suppression and cancer biology overall.

乳腺癌1型易感性（BRCA 1）蛋白是由同名的肿瘤抑制基因BRCA 1编码的蛋白质。虽然涉及几个细胞过程，如凋亡，细胞周期检查点的激活，泛素化和转录调控，该项目将主要集中在BRCA 1在DNA损伤反应（DDR）中的作用。BRCA 1蛋白具有串联重复的功能结构域，BRCA 1 C-末端结构域（BRCT）。BRCA 1的BRCT结构域特别令人感兴趣，因为蛋白质的结构排列形成裂缝，使得N-末端重复序列上的磷酸化丝氨酸的结合口袋和C-末端重复序列上的苯丙氨酸结合疏水口袋成为可能。BRCA 1与含有pSPxF基序的磷酸化蛋白质伴侣结合的能力是BRCA 1在DNA修复和肿瘤抑制中发挥作用所必需的。为了研究这些蛋白质-蛋白质相互作用的机制并探测BRCA 1在细胞环境中的功能，该项目将利用一系列Affimer蛋白作为BRCA 1野生型和突变型的结合伴侣。可以阐明BRCA 1的DDR机制的工作流程的开发可以应用于具有BRCT结构域的其他蛋白质，以了解这些结构域在DDR，肿瘤抑制和癌症生物学中的更广泛的生物学意义。