Defining the role of BARD1 in nucleosomal ubiquitylation

定义 BARD1 在核小体泛素化中的作用

• 批准号: 10368107
• 负责人: PETER S BRZOVIC
• 金额: $ 52.72万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10368107
• 关键词: Address; Ankyrin Repeat; Architecture; BARD1 gene; BRCA1 Protein; BRCA1 gene; BRCT Domain; Behavior; Binding; Biochemical; Biological; Biophysics; Breast Cancer Patient; Cell physiology; Cells; Chemicals; Clinical; Complex; Cryoelectron Microscopy; DNA; DNA Repair; Detection; Deuterium; Disease; EMSA; Genes; Goals; Hereditary Malignant Neoplasm; Histone H2A; Histones; Hydrogen; Knowledge; Learning; Length; Ligase; Malignant neoplasm of ovary; Modification; Molecular; Molecular Conformation; Mutation; Nucleosomes; Patients; Phenotype; Poly Adenosine Diphosphate Ribose; Positioning Attribute; Predisposition; Proteins; Reporting; Resected; Resolution; Role; Site; Structure; Tail; Testing; Transcriptional Regulation; Tumor Suppressor Proteins; Ubiquitin; Work; biophysical techniques; cancer predisposition; crosslink; design; gene repression; homologous recombination; insight; loss of function; malignant breast neoplasm; mutant; recruit; shared attention; ubiquitin-protein ligase

PROJECT SUMMARY BARD1 (BRCA1-Associated RING Domain protein-1) is an essential partner of the breast and ovarian cancer tumor-suppressor protein, BRCA1, and is included in a panel of genes used to evaluate patients with suspected hereditary cancer predisposition, especially breast and ovarian cancers. Despite this, little is known about the cellular role of BARD1. This project aims to address this serious gap in knowledge by defining at a molecular level how BARD1 contributes to DNA damage repair and to transcriptional repression. An ultimate goal is to enable predictions regarding potential loss-of-function phenotypes for mutations identified in patients. BRCA1 and its obligate partner BARD1 form a heterodimeric complex that is implicated in numerous cellular processes, most notably, transcriptional regulation and DNA repair via homologous recombination. The sole enzymatic activity directly associated with the BRCA1/BARD1 complex is as an E3 Ubiquitin ligase. The RING domains of BRCA1 and BARD1 specifically and uniquely target positions on the tail of nucleosomal histone H2A. The ability of BRCA1/BARD1 to place these Ub marks is essential to both its transcriptional repression of certain genes and its function in DNA damage repair by homologous recombination. While the RING of BRCA1 is required for all ligase activity, breast cancer patient mutations in the RING of BARD1 display loss-of-function specifically for ubiquitylation of H2A. A newly determined cryo-EM structure of the BRCA1/BARD1 RING domains sitting atop a nucleosome reveals that BARD1 dictates the orientation of the E3 ligase and, therefore, determines the site(s) of modification on H2A. In this project, we will build on this exciting new structural insight to address how regions outside BARD1’s RING contribute to its function as an essential partner of BRCA1.

项目总结