Homologous Recombination and Crosslink Repair

该项目（Homembrandation和Crosslink修复）整合到SBDR计划 通过关注对DMA加倍的整体细胞反应的病变去除步骤来进行项目 链断裂和链间交联。遗传学研究表明，同源的 双链断裂和交联修复途径中的重组。有充分的证据表明 同源重组修复（HRR）和伴随DNA损伤信号传导反应， 对基因组的维持至关重要这些生物途径的失调导致了几种 癌症和易患癌症的疾病，包括家族性乳腺癌和卵巢癌 （BRCA 1和BRCA 2）、范可尼贫血（FANCD 2和BRCA 2）和共济失调毛细血管扩张症（ATM）。 与其他DNA修复系统一样，HRR需要大量的蛋白质-蛋白质和蛋白质-配体 交互.我们的研究项目致力于破译 调节HRR和交联去除效率的相互作用。为了实现我们的目标， 将在四个目标下进行合作研究。具体而言，我们将（1） 确定Rad 51所需的Rad 52重组介体活性的分子基础 （2）阐明Rad 51与Pir 51相互作用的意义 以及BRCA 2外显子27，（3）检测FANCD 2和ATM之间的生化相互作用， 确定FANCD 2在Rad 51介导的反应中的作用，以及（4）确定复合物的基础 组装涉及BARD 1及其伴侣蛋白，并确定BRCA 1的影响- BARD 1复合物对Rad 51重组酶活性的影响。

The Project (Homologous Recombination and Crosslink Repair) integrates into the SBDR Program Project by focusing upon the lesion removal step of the overall cellular response to DMA double strand breaks and interstrand crosslinks. Genetic studies have shown a pivotal role of homologous recombination in double-strand break and crosslink repair pathways. There is ample evidence that homologous recombination repair (HRR) and companion DNA damage signaling reactions are critical for genome maintenance. Deregulation of these biological pathways leads to several cancers and diseases predisposing to cancer, including familial breast and ovarian cancers (BRCA1 and BRCA2), Fanconi anemia (FANCD2 and BRCA2), and Ataxia telangiectasia (ATM). As with other DNA repair systems, HRR entails extensive protein-protein and protein-ligand interactions. Our research project strives to decipher the molecular basis of the hierarchy of interactions that modulate the efficiency of HRR and crosslink removal. To achieve our objectives, collaborative studies described under four Aims will be carried out. Specifically, we will (1) determine the molecular basis of the Rad52 recombination mediator activity needed for Rad51 presynaptic filament assembly, (2) delineate the significance of the interactions of Rad51 with Pir51 and also BRCA2 Exon 27, (3) examine the biochemical interaction between FANCD2 and ATM and define the role of FANCD2 in Rad51-mediated reactions, and (4) determine the basis for complex assemblies involving BARD1 and its partner proteins and define the influence of the BRCA1- BARD1 complex on the Rad51 recombinase activity.