Therapeutic potential of FANCM for BRCA1-linked cancer

FANCM 对 BRCA1 相关癌症的治疗潜力

• 批准号: 10584591
• 负责人: Arvind Panday
• 金额: $ 9.95万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10584591
• 关键词: BRCA1 gene; Biochemical; CRISPR/Cas technology; Cancer cell line; Cells; Chromatin; Chromosome Structures; Chromosomes; Cytogenetics; DNA; DNA Damage; DNA Structure; DNA replication fork; Defect; Environment; Escherichia coli; Event; FANCD2 protein; Fanconi' s Anemia; Gene Conversion; Genes; Genetic; Genetic study; Genomic Instability; Goals; Hereditary Breast and Ovarian Cancer Syndrome; Histones; Human; Individual; Knock-out; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Cell; Mammalian Chromosomes; Mediating; Molecular; Motor; Mus; Mutation; Nucleosomes; Outcome; Pathway interactions; Pharmaceutical Preparations; Phase; Phenocopy; Phenotype; Play; Point Mutation; Poly(ADP-ribose) Polymerase Inhibitor; Positioning Attribute; Process; Protein Dynamics; Proteins; Regulation; Reporter; Resistance development; Role; Site; Small Interfering RNA; Source; Specificity; Susceptibility Gene; System; Techniques; Therapeutic; Woman; Work; cancer cell; cancer genome; cancer predisposition; cancer therapy; embryonic stem cell; genome-wide; holistic approach; homologous recombination; knock-down; malignant breast neoplasm; mutant; novel; novel therapeutics; prevent; recruit; repaired; response; success; synthetic lethal interaction; targeted cancer therapy; therapeutic target; tool; translocase; tumor; tumorigenesis

Project Summary/Abstract Breast and ovarian cancer are among the most common cancers in women worldwide.PARP inhibitors have shown potential for the treatment of BRCA-linked cancer, via a synthetic lethality mechanism that exploits the HR defect. However, tumors often develop resistance to these and other drugs. Therefore, there is a pressing need to find new, targeted treatments for BRCA-linked cancer. Genomic instability is a hallmark of cancer cells and a potential source of tumorigenesis. A major cause of genomic instability is replication fork stalling at sites of DNA damage or abnormal DNA structure. A limitation in the study of mammalian stalled fork repair has been a dearth of tools with which to analyze this process in molecular detail. The Scully lab solved this problem by adapting the Escherichia coli Tus/Ter replication fork barrier (RFB) to induce site-specific replication fork stalling on a mammalian chromosome. Tandem duplications (TDs) in primary cells lacking BRCA1 are induced specifically by a Tus/Ter block but not by a conventional double strand break (DSB), indicating specificity for the stalled fork response. Intriguingly, breast and ovarian cancers lacking BRCA1 similarly acquire large numbers of small (~10 kb) TDs, which we have termed “Group 1” TD. Thus, the Tus/Ter system recapitulates the BRCA1-specific regulation of Group 1 TD formation observed in human breast and ovarian cancer. I found that the stalled fork motor protein—FANCM (product of the Fanconi anemia [FA] group M gene) acts synergistically with BRCA1 to suppress Tus/Ter-induced TDs. Further, I discovered a novel synthetic lethal interaction between Brca1 and Fancm loss in mouse embryonic stem (ES) cells and in breast and ovarian cancer cells. These findings suggest that FANCM may be a promising therapeutic target in BRCA1-linked breast and ovarian cancer. My goals in this proposal are to delineate the novel FANCM-BRCA1 synthetic lethal interaction in cancer cells and to determine the mechanism of synthetic lethality (Aim1). Further, I will explore the chromatin environment and protein dynamics at the stalled fork and will study how alterations in these processes contribute to the FANCM-BRCA1 synthetic lethal interaction (Aim2). I observe an epistatic role of Fancm and its downstream target Fancd2 at Tus/Ter in promoting error free repair and suppressing error-prone repair.This critical role of Fancm and Fancd2 in repair pathway choice at stalled forks raises the possibility that they might share similar genetic interactions with Brca1. will identify how individual domains of FANCD2 function in repair pathway choice at stalled forks and their genetic interaction with Brca1 (Aim 3). This holistic approach will provide a full picture of the mechanism of FANCM-BRCA1 synthetic lethal interactions and might identify in FANCD2 a new synthetic lethal target for cancer therapy. I

项目总结/文摘