IMPLICATIONS OF DNA REPLICATION FORK PROTEINS FOR CANCER

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 癌细胞的一个共同特征是基因组不稳定。为了实现正常发育，细胞必须准确协调影响DNA复制、染色体分离和DNA损伤修复的途径。这些过程中的任何一个过程中的事故都可能导致基因组的不稳定，并最终导致癌症发展的更高发生率。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，有特定的分子连接这些途径，以确保协调调节。其中许多分子在DNA复制和修复以及染色体分离方面具有重叠的功能。这项研究的重点是RecQ解旋酶超家族蛋白质的功能，在DNA修复和染色体分离中发挥作用。 Bloom综合征是一种由Bloom综合征基因(BLM)突变引起的隐性疾病，其特征是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提炼BLM负责与已知DNA修复和复制蛋白建立伙伴关系的亚域，以阐明BLM在基因组稳定性中的确切作用。此外，Chl1p是最近在果蝇中发现的一个新的RecQ家族成员，它与DNA复制和染色体结合有关。这项研究将通过基因缺失Chl1p的整个ORF来鉴定Chl1p在果蝇中的功能。总体而言，这些实验跨越了生物化学、分子生物学和遗传学的学科，以调查RecQ蛋白伙伴关系，该伙伴关系负责通过DNA复制、修复和染色体分离进行准确的进展。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 of the entire ORF for 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.