IMPLICATIONS OF DNA REPLICATION FORK PROTEINS FOR CANCER

DNA 复制叉蛋白对癌症的影响

• 批准号: 8360071
• 负责人: Karen H. Almeida
• 金额: $ 18.65万
• 依托单位: UNIVERSITY OF RHODE ISLAND
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360071
• 关键词: Affect; BLM gene; Behavioral Research; Biochemical; Biochemistry; Biomedical Research; Bloom Syndrome; Cells; Chromosome Segregation; DNA Repair; DNA biosynthesis; DNA replication fork; Deletion Mutation; Development; Discipline; Disease; Drosophila genus; Family member; Funding; Genetic; Genome; Genome Stability; Genomic Instability; Grant; Incidence; Lead; Malignant Neoplasms; Molecular Biology; Molecular Genetics; Mutation; National Center for Research Resources; Pathway interactions; Principal Investigator; Procedures; Proteins; RecQ protein; Regulation; Research; Research Infrastructure; Resources; Role; Source; United States National Institutes of Health; cancer cell; cohesion; cost; helicase; member; protein function; repaired; research study

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. A unifying feature of cancer cells is an unstable genome. To achieve normal development, a cell must accurately coordinate pathways affecting DNA replication, chromosome segregation and DNA damage repair. Mishaps in any of these procedures can lead to instability in the genome and ultimately to a higher incidence of cancer development. Therefore, these mechanisms must be highly orchestrated and rigorously regulated. Accumulating evidence demonstrates that there are particular molecules that bridge these pathways to insure coordinate regulation. Many of these molecules have overlapping functions for DNA replication and repair and chromosome segregation. This study focuses on members of the RecQ helicase superfamily of proteins that function at replication forks and have roles in DNA repair and chromosome segregation. Bloom Syndrome is a recessive disorder resulting from mutation in the Bloom Syndrome gene (BLM) and characterized by increased genomic instability and enhanced onset of cancer. The physical and functional biochemical studies undertaken will identify and refine the sub-domains of Blm responsible for partnerships with known DNA repair and replication proteins to clarify the exact role of Blm in genomic stability. Furthermore, Chl1p is a newly identified RecQ family member in Drosophila and is implicated in bridging DNA replication and chromosomal cohesion. This study will identify the function of Chl1p in Drosophila by genetic deletion and mutations in Chl1p. Overall, the experiments span the disciplines of biochemistry, molecular biology and genetics to investigate the RecQ protein partnerships responsible for the accurate progression through DNA replication, repair and chromosome segregation.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 子项目的主要研究者可能是由其他来源提供的， 包括其他NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 癌细胞的一个统一特征是不稳定的基因组。为了实现正常发育，细胞必须精确地协调影响DNA复制、染色体分离和DNA损伤修复的途径。这些程序中的任何一个失误都可能导致基因组的不稳定，并最终导致癌症发生率更高。因此，这些机制必须高度协调和严格监管。越来越多的证据表明，有特定的分子，桥梁这些途径，以确保协调调节。这些分子中的许多具有重叠的DNA复制和修复以及染色体分离的功能。这项研究的重点是RecQ解旋酶超家族的蛋白质，在复制叉的功能，并在DNA修复和染色体分离的作用。 Bloom综合征是由Bloom综合征基因（BLM）突变引起的隐性疾病，其特征在于基因组不稳定性增加和癌症发病增加。所进行的物理和功能生化研究将确定和完善负责与已知DNA修复和复制蛋白的伙伴关系的Blm的子域，以澄清Blm在基因组稳定性中的确切作用。此外，Chl 1 p是果蝇中新鉴定的RecQ家族成员，并涉及桥接DNA复制和染色体凝聚。本研究将通过Chl 1 p基因的缺失和突变来鉴定Chl 1 p在果蝇中的功能。总的来说，这些实验跨越了生物化学，分子生物学和遗传学的学科，以研究负责通过DNA复制，修复和染色体分离准确进展的RecQ蛋白伙伴关系。