DNA REPLICATION CONTROL AND ITS APPLICATION TO SELECTIVE KILLING OF CANCER CELLS
Wenge Zhu, Assistant Professor
George Washington University, 2121 Eye St Nw, Ste 601, Washington, Dc 20052
Grant 4R00CA136555-02 from National Cancer Institute
Abstract: Maintenance of genome stability is extremely important in the cell cycle, with genomic instability being the hallmark of cancer cells. DNA re-replication is one type of genomic instability with replication origins firing multiple times during the same cell cycle. Although several genes that regulate DNA re-replication have been identified, the mechanisms behind them remain to be determined. Moreover, whether DNA re-replication control can be used for cancer therapy is unknown. The aim of this proposal is to investigate the mechanisms by which Cdk1 prevents DNA re-replication during G2/M phase in both human cancer and normal cells, to screen for small molecules that selectively cause DNA re-replication in cancer cells, and to perform genome-wide studies of DNA re-replication control. This study will be useful not only to understand one facet of how our cells maintain a stable genome, but also to provide us with useful therapeutic targets and potential compounds for the treatment of cancer. Therefore, this proposal is relevant to the mission of NIH/NCI in its pursuit of fundamental knowledge about living systems and supporting research, training, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. The Specific Aims of this proposal are Aim 1. Investigate the role of Cdkl in regulating Orel activity to prevent DNA re-replication during G2/M. In particular, we will investigate the role of phosphorylation of Orel by Cdk1 kinases during G2/M and whether Orel is involved in re-replication regulation during G2/M. Aim 2. Screen for small molecules by a HTS assay to identify small compounds that selectively cause DNA rereplication in cancer cells. Aim 3. Perform cell-based genome-wide studies of DNA re-replication control via a HTS assay by siRNA transfection to identify new genes that involve in DNA re-replication control. My ultimate career goal is to become an independent researcher in the field of cancer research. To accomplish this, currently I am investigating the mechanisms that cause genome instability in cancer cells and its application for cancer therapy, resulting in the application for this award
Keywords: Animals; Apoptosis; Apoptosis Pathway; Assay; Automobile Driving; Award; Bioassay; Biologic Assays; Biological Assay; CDC2 Protein Kinase; CDK; CDK1; Cancer Treatment; Cancers; Categories; Cell Cycle; Cell Cycle Arrest; Cell Cycle Controller cdc2; Cell Death, Programmed; Cell Division Control Protein 2 Homolog; Cell Division Cycle; Cell Division Cycle 2; Cell Division Cycle 2 Protein; Cell division; Cells; Chemicals; Collaborations; Cyclin-Dependent Kinase 1; Cyclin-Dependent Kinases; Cyclin-Dependent Protein Kinases; DNA; DNA Damage; DNA Injury; DNA Replication; DNA Synthesis; DNA biosynthesis; Data; Deoxyribonucleic Acid; Diagnosis; Drivings, Automobile; Drugs; EC 2.7; Ensure; Forecast of outcome; Future; G2 Phase; G2 period; GMNN protein, human; GWAS; Gap Phase 2; Geminin; Gene Amplification; Gene Copy Number; Gene Dosage; Gene Targeting; Genes; Genome; Genome Instability; Genome Stability; Genomic Instability; Genomics; Goals; Grant; High Throughput Assay; Human; Human Genome; Human, General; Investigators; Killings; Kinases; Knowledge; Libraries; Life Support Systems; M Phase; M phase (cell cycle); Maintenance; Maintenances; Malignant Cell; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Neoplasms; Malignant Tumor; Man (Taxonomy); Man, Modern; Medication; Mission; Mitosis; Mitosis Stage; NIH; National Institutes of Health; National Institutes of Health (U.S.); Normal Cell; Pathogenesis; Pathway interactions; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase Transition; Phosphorylation; Phosphotransferases; Play; Position; Positioning Attribute; Prevention; Prognosis; Programs (PT); Programs [Publication Type]; Protein Phosphorylation; RNA, Small Interfering; Regulation; Regulatory Pathway; Replication Origin; Research; Research Personnel; Research Training; Researchers; Role; Screening procedure; Second Gap Phase; Small Interfering RNA; Solid Neoplasm; Solid Tumor; Stability, Genomic; Targetings, Gene; Time; Transfection; Transphosphorylases; United States National Institutes of Health; Work; anticancer research; anticancer therapy; base; cancer cell; cancer research; cancer therapy; career; cdc2 gene product; cdc2+ Protein; cdk Proteins; cdk1 Kinase; driving; drug candidate; drug/agent; expectation; geminin, DNA replication inhibitor protein, human; genome wide association scan; genome wide association studies; genome wide association study; genome-wide; genome-wide scan; genomewide association scan; genomewide association studies; genomewide association study; genomewide scan; high throughput screening; in vivo; inhibitor; inhibitor/antagonist; malignancy; natural gene amplification; neoplasm/cancer; novel; ori Region; outcome forecast; p34 (cdc2); p34 Protein Kinase; p34CDC2; pathway; prevent; preventing; programs; screening; screenings; siRNA; small molecule; social role; success; therapeutic target; tumor; whole genome association studies; whole genome association study
Relevance: Almost all human tumors display genome instability. The proposed work promises to provide not only an understanding of the mechanisms by which human cells maintain their genome stability, and the application of these mechanisms to selective killing of cancer cells, but also the potential compounds and new targets for cancer therapy
Project start date: 2010-03-05
Project end date: 2013-02-28
Budget start date: 5-MAR-2010
Budget end date: 28-FEB-2011
PFA/PA: PA-06-133
4R00CA136555-02 (2010): $248999
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