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The role of PRMT5 in preventing intra-chromosomal deletions in cancer cells

PRMT5 在预防癌细胞染色体内缺失中的作用

基本信息

批准号：
10728560
负责人：
Renee Bouley
金额：
$ 7.88万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10728560
关键词：
Acetyltransferase Active Sites Affect Automobile Driving BRCA1 gene BRCA2 gene Biochemical Biological Assay Biological Models Catalogs Cell Cycle Cell Proliferation Cells Chromosomal Rearrangement Chromosome Deletion Chromosome abnormality Complex DNA Damage DNA Double Strand Break DNA Repair DNA annealing Data Development Direct Repeats Double Strand Break Repair Elements Enzymes Eukaryota Event Evolution Excision Fission Yeast Frequencies Gene Expression Regulation Generations Genes Genetic Genetic Recombination Goals HTATIP gene Histones Homology Modeling Human In Vitro Link Malignant Neoplasms Maps Mediating Methylation Methyltransferase Mitosis Modeling Mutate Mutation Mutation Analysis Mutation Detection Nonhomologous DNA End Joining Pathogenicity Pathway interactions Peptides Pharmaceutical Preparations Post-Translational Protein Processing Process RAD52 gene Repetitive Sequence Reporting Role S phase Side Somatic Mutation Techniques Testing Validation Work Yeasts analog arginine methyltransferase artificial intelligence algorithm brca gene cancer cell carcinogenesis chromatin remodeling design driver mutation enzyme activity experimental study gene repair genetic information homologous recombination in vivo innovation metaplastic cell transformation mutant neoplastic cell prevent recombinational repair repaired response small molecule inhibitor yeast genetics

项目摘要

Project Summary/Abstract PRMT5 is an arginine methyltransferase with key roles in cancer. The gene has pleiotropic functions ranging from gene regulation and development to modulation of DNA double strand break (DSBs) repair. In S-phase and mitosis, DSBs are repaired primarily by homologous recombination (HR) a process in which missing genetic information is copied from another undamaged chromosomal region. In humans, error-free HR is mediated by BRCA1, BRCA2 and RAD51. RAD52, an accessory gene, facilitates an error-prone HR sub-pathway that can produce intrachromosomal deletions (ICDs). PRMT5 appears to modulate chromatin remodeling at the DSB through the error-free BRCA1/2-RAD51 pathway. In fission yeast (S. pombe), we identified physical and genetic interactions between PRMT5 and RAD52. Deletion of PRMT5 increases the frequency of ICDs while deletion of RAD52 decreases ICDs suggesting that they have opposite functions. In cancer cells PRMT5 mutations increases the size of ICDs. Using artificial intelligence algorithms, we discovered multiple likely pathogenic mutations including three driver mutations in the active site of PRMT5 that are likely to destabilize the function of the enzyme. We hypothesize that PRMT5 inhibits ICDs by biasing repair of DNA double strand breaks toward conservative pathways. We developed innovative in vivo assays to probe HR repair mechanisms that produce ICDs. The repair mechanisms and factors involved are conserved from yeast to humans making the S. pombe model system highly tractable. A homology analysis reveals that all identified human mutated residues are present in yeast. In Aim1 we will place PRMT5 in the DNA damage repair epistatic pathway using mutational analysis and sensitivity to various DNA damage drugs. Additionally, we will employ in vivo repair assays to understand the HR pathways by which ICDs are produced in the absence of the PRMT5 function. In Aim 2 we will analyze PRMT5 mutations identified in cancer cells using the Catalogue of Somatic Mutations in Cancer (COSMIC). We will employ modeling techniques and enzymatic assays to test how these mutations affect the enzymatic function of PRMT5 and DSB repair. Most of these mutations are conserved in yeast making this analysis tractable. The findings will be further validated in human cells.

项目总结/文摘