Mechanisms of Genome Integrity

基因组完整性的机制

• 批准号: 10375574
• 负责人: Eric C Greene
• 金额: $ 55.2万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10375574
• 关键词: Address; BRCA2 gene; Cells; Chromosomal Rearrangement; Chromosomes; Complex; DNA; DNA Damage; DNA Double Strand Break; DNA Repair; DNA biosynthesis; Defect; Embryo; Event; Genes; Genetic Predisposition to Disease; Genome; Goals; Hereditary Malignant Neoplasm; Human; Individual; Lead; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Microscopy; Monitor; Mus; Mutation; Natural regeneration; Optics; Outcome; Pathway interactions; Process; Proteins; Rad51 recombinase; Regulation; Research; Sequence Homologs; Single-Stranded DNA; Technology; Time; ds-DNA; genetic information; genome integrity; homologous recombination; malignant breast neoplasm; prevent; programs; recruit; repaired; single molecule

PROJECT SUMMARY Our chromosomes are constantly bombarded with a variety of insults, resulting in damage that must be repaired. Cells have evolved mechanisms to detect and repair broken strands of DNA, thereby preventing loss of important genetic information. Double‐stranded DNA breaks (DSBs) are a type of damage that lead to particularly disastrous outcomes. If not corrected, DSBs can cause gross chromosomal rearrangements, which are the hallmark of all forms of cancer. Homologous recombination (HR) is a conserved pathway that cells can use to repair DSBs, and HR is necessary to prevent and repair the damage that arises during DNA replication. When a DSB occurs, the DNA ends are processed to generate 3' single‐strand DNA (ssDNA) overhangs. The ssDNA ends then pair with homologous sequence elsewhere in the genome, and the missing DNA is replaced using the homologous DNA as a template for replication. Finally, the replicated intermediate is resolved, regenerating the continuity of the broken DNA. HR requires the coordinated action of a complex repertoire of proteins, which are responsible for sensing damage, recruiting essential factors, and processing and repairing the damaged DNA. The consequences of disrupting HR are devastating. For example, mutations in the RAD51 recombinase are embryonic lethal in mice, and mutations in human RAD51 are linked to breast cancers. In addition, defects in BRCA2 account for at least 5% of all breast cancers and also confer a genetic predisposition to ovarian cancer. BRCA2 is thought to help regulate HR, and loss of this regulation may be the reason why this gene is linked to hereditary cancers. New discoveries will be necessary to fully understand the mechanistic basis for these outcomes. Our research program is focused on understanding how proteins sense and respond to damaged DNA and they then repair the damaged DNA to prevent mutations that can lead to cancer. To help address these problems we have developed unique technologies that allow us to directly visualize hundreds of individual molecules using optical microscopy, which enables us to monitor the spatial and temporal progression of DNA repair and DNA replication in real‐time at the single‐molecule level. Using this approach, we seek to define the fundamental mechanisms that our cells use to replicate and repair DNA, with the long‐term goal of understanding how errors during these processes can lead to chromosomal rearrangements.

项目总结