Restoring genome stability and tumor suppression in BRCA1 deficient cells

恢复 BRCA1 缺陷细胞的基因组稳定性和肿瘤抑制

• 批准号: 10064997
• 负责人: RICHARD J BAER
• 金额: $ 52.35万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10064997
• 关键词: Address; Animal Model; BRCA mutations; BRCA1 Mutation; BRCA1 Protein; BRCA1 gene; BRCA2 Protein; BRCA2 gene; Biological; Breast; Breast Carcinoma; Breast Epithelial Cells; Cell physiology; Cells; Chromosome abnormality; Chromosomes; Clinical; DNA; DNA Damage; DNA Double Strand Break; DNA biosynthesis; DNA replication fork; Data; Elements; G2 Phase; Genetically Engineered Mouse; Genome; Genome Stability; Genomic Instability; Germ-Line Mutation; Hereditary Breast Carcinoma; Hereditary Breast and Ovarian Cancer Syndrome; Inherited; Intervention; Lead; Lesion; Maintenance; Malignant Neoplasms; Malignant neoplasm of ovary; Mammary Neoplasms; Mediating; Mediator of activation protein; Modeling; Molecular; Mutant Strains Mice; Normal Cell; Ovarian; Pathogenicity; Pathway interactions; Patients; Predisposition; Process; Property; Proteins; S Phase; Serous; Testing; Therapeutic; Tumor Suppression; Tumor Suppressor Genes; Tumorigenicity; Woman; brca gene; ds-DNA; genome integrity; homologous recombination; in vivo; malignant breast neoplasm; mutant; mutation carrier; novel; nuclease; preservation; prophylactic; reconstitution; repaired; replication stress; response; therapeutic target; translocase; tumor; ubiquitin-protein ligase

PROJECT SUMMARY/ABSTRACT: As central mediators of the DNA damage response, the BRCA1 and BRCA2 proteins normally act to preserve genome integrity. Indeed, their genome maintenance functions are thought to be a major, if not the principal, means by which BRCA1/2 suppress tumor formation in normal cells. In particular, BRCA1 and BRCA2 are required for double-strand DNA break repair by homologous recombination (DSBR-HR). However, recent studies have uncovered another BRCA1/2 function that also preserves genome stability and thus potentially contributes to the tumor suppression activity of both proteins. During DNA replication, BRCA1 and BRCA2 have been shown to promote genome integrity by protecting stalled replication forks (SRFs) from nucleolytic degradation. These findings raise critical questions regarding the mechanisms of BRCA1/2 tumor suppression and the prospects for therapeutic targeting of the BRCA1/2 pathway. For example, is the tumor suppression activity of the BRCA1/2 pathway mediated through its ability to promote DSBR-HR or SRF stability, or both? Also, can the DSBR-HR or SRF stability functions of BRCA1/2 be restored for prophylactic and/or therapeutic purposes in women who carry BRCA1/2 mutations? Our preliminary studies have uncovered a novel mechanism by which SRF stability can be reconstituted in BRCA1 mutant cells. In particular, we show that depletion of SMARCAL1, a DNA translocase implicated in replication fork dynamics, restores both SRF stability and chromosome integrity in BRCA1-deficient cells subjected to replication stress. On the basis of these results, we hypothesize that inappropriate remodeling of replication forks by SMARCAL1 in BRCA1- deficient cells can increase genome instability and thereby predispose these cells to breast cancer. To test these hypotheses, we will 1) define the mechanisms by which SMARCAL1 inactivation rescues SRF stability and chromosomal integrity in BRCA1-deficient cells, and 2) determine whether tumor suppression activity can be restored to BRCA1-mutant cells by SMARCAL1 inhibition.

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