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FANCJ dependent pathways in replication stress

复制应激中的FANCJ依赖性途径

基本信息

批准号：
10012292
负责人：
Sharon B Cantor
金额：
$ 3.69万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-05 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10012292
关键词：
Acetylation Address BRCA1 gene BRCA2 gene Binding Biochemical Genetics Bioinformatics Biological Assay Breast Breast Cancer gene Bypass Cancer Patient Cell Proliferation Cell Survival Cells Cisplatin Clinical Complex DNA DNA Damage DNA Mismatch Repair Protein MLH1 DNA Repair DNA Repair Gene DNA Structure DNA biosynthesis DNA lesion DNA replication fork Data Defect Disease Electron Microscopy Engineering Ensure Equilibrium Fanconi Anemia-BRCA Pathway Fanconi anemia protein Fanconi&apos s Anemia Fiber Functional disorder Genes Genome Genomic Instability Goals Health Hereditary Breast Carcinoma Hereditary Breast and Ovarian Cancer Syndrome Knowledge Link MLH1 gene Malignant Neoplasms Malignant neoplasm of ovary Mismatch Repair Modification Molecular Mutate Mutation Null Lymphocytes Oncogenes Outcome Pathway interactions Patients Phenotype Phosphorylation Play Process Proteins Proteomics Recovery Regulation Research Resistance Role SMARCA3 gene Site Stress Supporting Cell Testing Therapeutic Therapeutic Intervention Transitional Cell Translations Tumor Suppression biological adaptation to stress chemotherapy gain of function gene function genetic approach genome integrity helicase improved innovation insight mutant repaired replication stress single molecule therapeutic development transcription factor tumor

项目摘要

Project Summary: Great progress has been made in uncovering the proteins and pathways that function in the replication stress response. In particular, the hereditary breast cancer genes, as well as genes mutated in Fanconi anemia (FA) function in the replication stress response. It is now understood that loss of their function in the replication stress response contributes to the sensitivity of associated tumors to chemotherapies, such as cisplatin. However, the distinct functions for the BRCA-FA proteins are largely unknown. Here, we propose to analyze DNA replication fork dynamics, replisome components, and identify patient mutations that have specific defects in the replication stress response. To define how a cell transitions from defective to dysregulated replication, we have engineered cells expressing different mutant versions of the BRCA1-associated FANCJ also mutated in breast/ovarian cancer and FA. Similar to BRCA1, we have uncovered that FANCJ functions to protect replication forks from collapse. We also found that this FANCJ fork protection function requires its direct interaction with the mismatch repair (MMR) protein, MLH1. This finding provides insight as to why cells lacking the FANCJ-MLH1 interaction fail to recover from replication stress. We have also identified putative gain-of-function FANCJ mutants, such as the BRCA1-interaction defective mutant, that circumvent replication stress, keep forks intact, and confer hyper- resistance to replication stress inducing agents. In Aim 1, we will seek to define how FANCJ interactions direct DNA replication fork dynamics. Given that FANCJ localizes to replication forks, displaces proteins, and unwinds DNA, we hypothesize that disrupted vs dysregulated replication will reflect not only changes in DNA structures, but also the proteins found at DNA replication forks. In Aim 2, we will seek to determine how FANCJ contributes to the composition of the replisome in both unchallenged and at stressed replication forks. Replication stress induces changes to FANCJ protein interactions and post-translation modifications. Some of these changes occur at sites we found to be mutated in cancer patients. In Aim 3, we will seek to generate FANCJ mutants resistant to replication stress induced changes to uncover mechanisms regulating FANCJ function that are lost in cancer. Collectively, by defining how cells succumb to- or survive- toxic DNA damage that normally interferes with replication, we will gain insight towards mechanisms transitioning cells from defective to dysregulated replication in cancer. !

项目总结: