Investigating contributions of BRCA2 DNA-binding domains toward maintaining genome integrity

研究 BRCA2 DNA 结合域对维持基因组完整性的贡献

• 批准号: 10593891
• 负责人: Francisco Neal
• 金额: $ 4.46万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593891
• 关键词: Affect; Affinity; Attenuated; Binding; Biochemical; Biological; Biological Process; Biophysics; Breast; C-terminal; Cancer Biology; Cancer Etiology; Cause of Death; Cells; Chromatids; Complex; DNA; DNA Binding; DNA Binding Domain; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Repair Disorder; DNA Sequence Alteration; DNA Structure; DNA biosynthesis; DNA replication fork; DNA-Binding Proteins; Data; Defect; Development; Double Strand Break Repair; Exhibits; Fanconi' s Anemia; Fellowship; Filament; Fostering; Foundations; Future; Gene Mutation; Genetic; Genetic Recombination; Genetic study; Genome; Genome Stability; Genomic Instability; Germ-Line Mutation; Impairment; Inherited; Invaded; Knowledge; Lead; Left; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Mediator; Methods; Mutation; Neoplastic Cell Transformation; Nucleoproteins; Ovarian; Pancreas; Pathway interactions; Physicians; Play; Predisposition; Process; Rad51 recombinase; Research; Research Personnel; Role; Scientist; Single-Stranded DNA; Specificity; Structure; Syndrome; Testing; Therapeutic; Training; Treatment Protocols; Tumor Suppressor Proteins; United States; Variant; Work; biophysical analysis; cancer therapy; cancer type; clinically relevant; crosslink; defined contribution; design; ds-DNA; experimental study; genome integrity; homologous recombination; malignant breast neoplasm; neoplastic cell; novel; preservation; recombinational repair; replication stress; stem; success; synergism; tool; tumorigenesis

ABSTRACT Conserved mechanisms exist to eliminate DNA damage, which, if left unrepaired, can cause gene mutations and genome rearrangements to trigger neoplastic cell transformation and oncogenesis. In particular, homologous recombination (HR) represents a high-fidelity tool for the repair of DNA double-strand breaks (DSBs), interstrand crosslinks, and collapsed DNA replication forks. Proper execution of HR requires the tumor suppressor BRCA2 (Breast Cancer 2). Germline mutations in BRCA2 lead to breast and ovarian cancer and also the cancer-prone syndrome Fanconi anemia. Moreover, somatic driver BRCA2 mutations are found in a variety of cancer types. Further work is necessary to elucidate the mechanistic role of BRCA2 in HR repair. Importantly, the research proposed herein will help define the contributions of two distinct DNA binding domains toward the function of BRCA2 as a “recombination mediator,” specifically in facilitating the assembly of complexes of the RAD51 recombinase on single-stranded DNA derived from the processing of DSBs. Our central hypothesis posits that the two DNA-binding domains within BRCA2 play an essential role in guiding BRCA2-dependent DSB repair and replication fork preservation through the engagement of single-stranded DNA and DNA structures present in processed DSBs. We will conduct a variety of biochemical, genetic, and cell biological studies under two specific aims to test this central tenet. Throughout these experiments, we will delineate how genetic mutations within each DNA binding domain affect key aspects of HR and replication fork preservation. The results from this fellowship project will not only expand our understanding of how the BRCA2 DNA-binding domains contribute to the maintenance of genome stability, but they will also shed light on how mutations within these domains ultimately cause malignancy. Furthermore, we expect our findings to help identify new targets and pathway pivot points for the development of novel cancer therapeutics.

摘要