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Investigate role of microRNA cluster 183-96-182 in DNA repair and radiosensitivit

研究 microRNA 簇 183-96-182 在 DNA 修复和放射敏感性中的作用

基本信息

批准号：
8606431
负责人：
Dipanjan Chowdhury
金额：
$ 34.17万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-02-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8606431
关键词：
Address Algorithms Apoptosis Attenuated BRCA1 gene Biochemical Bioinformatics Biological Assay Blood Cells Breast Cancer Biology Cell Death Cell Differentiation process Cell Line Cells Chromosome Breakage Chronic Lymphocytic Leukemia Clinical Comet Assay DNA Damage DNA Double Strand Break DNA Repair DNA Repair Gene DNA Repair Pathway DNA repair protein Functional RNA Gastrointestinal tract structure Gene Expression Gene Targeting Goals Hematopoietic Housing In Vitro Interphase Cell Ionizing radiation Kidney Lung Malignant Neoplasms Measures Mediating Messenger RNA MicroRNAs Mitotic Molecular Profiling Monitor Neuraxis Nonhomologous DNA End Joining Normal Cell Ovary Pathway interactions Phenotype Production Prostate Proteins Pulsed-Field Gel Electrophoresis Radiation Radiation Tolerance Radiation therapy Reagent Reporter Resistance Resistance development Role Specificity System Transcript Transformed Cell Line attenuation cancer cell cancer therapy chemotherapeutic agent cytotoxic homologous recombination irradiation melanoma member neoplastic cell novel outcome forecast overexpression public health relevance repaired research study response therapy resistant tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Radiation and chemotherapeutic agents eradicate tumors by inducing irreparable DNA damage. However, cancer cells often develop resistance to therapy by manipulating the DNA repair machinery. Conversely, a dividing cell constantly exposed to environmental and endogenous DNA damaging agents can transform into a tumor due to incorrect repair. Therefore the expression level of DNA repair proteins is critical both for cancer therapy and tumorigenesis. In our preliminary studies we have discovered a novel connection between a new class of gene expression regulators, microRNAs and DNA repair proteins. MicroRNAs (miRNAs) are small non-coding RNAs that typically dampen gene expression. There is accumulating evidence that miRNAs are mis-expressed in cancer cells. It is noteworthy that ectopic overexpression of miRNAs downregulating DNA repair proteins could sensitize cancer cells to radiation and other genotoxic reagents. Alternatively, tumors that delete these miRNAs may develop resistance to conventional cancer therapy. DNA repair is a 'house keeping' function, and micro-RNA mediated attenuation of DNA repair may appear counter intuitive. However, normal cells down modulate DNA repair in a terminally differentiated state where overall DNA repair is downregulated. Using the experimental system of in vitro hematopoietic cell differentiation, we have identified microRNAs (miRNAs), miR-24 and a polycistronic miRNA cluster including miRNAs (183, 96, 182), that are upregulated in terminally differentiated non-dividing cells but are rapidly down regulated in response to ionizing radiation (IR) in dividing cells. We hypothesize that in post-mitotic cells DNA damage induces apoptosis and miRNAs attenuate the DNA repair machinery promoting cell death. Conversely, in response to IR the miRNAs are downmodulated in dividing cells to accentuate the production of DNA repair proteins and boost the DNA damage response. In support of this contention, we observed, that miR-24, downregulates the expression of a key DSB repair protein, H2AX and impedes DSB repair in terminally differentiated blood cells. The miRNAs (182,183 and 96) that we propose to study have already been noted for aberrant expression in a variety of tumors. A direct effect of these miRNAs on cancer could be by dysregulation of the DNA repair machinery. Bioinformatic predictions suggest that several DNA repair genes, such as, BRCA1, ATR, XLF, etc. are targeted by the miRNAs-183, 96 and 182. Preliminary experiments validate the prediction that miR-182 regulates BRCA1. In Aim #1 we will use different computational, and biochemical strategies, to identify and validate DNA repair factors targeted by miRNAs-183, 96 and 182 in transformed cell lines and primary cells. In Aim #2 we will systematically study the effect of these miRNAs on DSB repair and determine their impact on each repair pathway. Finally we will evaluate the radiosensitivity of cancer cells expressing these miRNAs. There is limited understanding of the role of miRNAs in DNA repair and this study will address this issue and also elucidate the impact of miRNAs on radiotherapy.

描述（由申请人提供）：