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Molecular analyses of RECQ1 functions in genome maintenance

RECQ1 在基因组维护中的功能的分子分析

基本信息

批准号：
8132562
负责人：
Sudha Sharma
金额：
$ 32.02万
依托单位：
HOWARD UNIVERSITY
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：
2010-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8132562
关键词：
Affinity Chromatography Aging Amino Acids Binding Biochemical Biological Biological Process Bloom Syndrome Catalytic Domain Cell Extracts Cell physiology Cells Characteristics Chromosomal Instability Clinical Complex Cruciform DNA DNA DNA Damage DNA Double Strand Break DNA Repair DNA Repair Pathway DNA Structure Defect Development Disease Educational Curriculum Ensure Event Family Foundations Frequencies Future Genetic Recombination Genome Genome Stability Genomic Instability Genotoxic Stress Goals Grant Growth Health Hela Cells Hereditary Disease Homologous Gene Human Immunoprecipitation In Vitro Individual Ionizing radiation Knock-out Knockout Mice Letters Life Link Maintenance Malignant Neoplasms Mass Spectrum Analysis Metabolism Mismatch Repair Modeling Molecular Mus Mutation Nature Organism Pathway interactions Patients Play Predisposition Premature aging syndrome Productivity Property Proteins Publishing RECQL gene RECQL4 gene RECQL5 gene Rare Diseases RecQ protein Recombinants Regulation Research Research Personnel Resources Role Rothmund-Thomson syndrome Sister Chromatid Exchange Site-Directed Mutagenesis Small Interfering RNA Testing United States National Institutes of Health Werner Syndrome Work cancer prevention clinical phenotype early onset helicase high risk homologous recombination in vitro activity insight member metaplastic cell transformation migration novel prevent public health relevance recombinational repair repaired response tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The RecQ helicase family is a group of highly conserved DNA unwinding enzymes critical in guarding genome stability in all kingdoms of life. Human RecQ homologs include RECQ1, BLM, WRN, RECQL4, and RECQ5. Although the five human RecQ proteins are similar in their catalytic core and share certain biochemical properties in vitro, they are clearly not redundant. Mutations in BLM, WRN and RecQ4 are associated with distinct genetic disorders of Bloom, Werner, and Rothmund-Thomson syndromes, respectively. Thus, a defect in one RecQ protein is sufficient to cause genomic instability that cannot be compensated by other RecQ homologs. However, what makes each RecQ protein unique is not understood. Dissecting the functions of each human RecQ helicase, and comparing the similarities and differences among them, will reveal which aspects of RecQ functions in DNA metabolism are essential for genome maintenance. The goal of this proposal is to examine molecular functions of RECQ1, the most abundant but least characterized human RecQ helicase homolog. Recently, we have shown that RECQ1 is essential for genome stability maintenance; its deficiency induces accumulation of DNA damage and chromosomal instability. RECQ1 binds and unwinds DNA structures that represent intermediates of DNA recombination repair, and interacts physically and functionally with proteins involved in regulating genetic recombination. Moreover, RECQ1-deficient cells are more sensitive to DNA damage and display spontaneously elevated sister chromatid exchanges reminiscent of aberrant repair of stalled replication forks. We hypothesize that RECQ1 plays critical roles in ensuring genome stability by virtue of its catalytic actions and specific interactions with cellular protein partners. To test this hypothesis, we are proposing systematic analyses of the biochemical and cellular characteristics of RECQ1. We will elucidate how biochemical activities of RECQ1 allow it to achieve its putative functions in genome stability maintenance by: 1) elucidating role(s) of RECQ1 in DNA repair pathways of genome stability maintenance; 2) determining critical amino acid residues of RECQ1 essential for specific catalytic and cellular functions; and 3) identifying novel protein interactions of RECQ1 using unbiased biochemical approaches and investing their functional significance. Results from these studies will be important to establish biological roles of RECQ1. This should facilitate dissecting the molecular details that explain similarities and differences in the biological functions of human RecQ helicases in pathways of genome stability maintenance to prevent cancer and premature aging. PUBLIC HEALTH RELEVANCE: RECQ1 belongs to the RecQ family of DNA helicases members of which are associated with rare diseases of premature aging and cancer predisposition in humans. Thus, the functions of RecQ helicases have a direct impact on human health. The presence of multiple RecQ homologs in humans indicates functional specialization; elucidating the molecular function(s) of RECQ1 helicase should, therefore, provide important insights to the mechanisms of genome stability maintenance that prevent development of cancer and early onset of aging.