Mechanistic Dissection of the Falconi Anemia Pathway of DNA Damage Response and Repair

项目摘要 来自Fanconi贫血(FA)途径的蛋白质在DNA修复中发挥着不可或缺的作用 重组(HR)。FA是一种多基因疾病，以进行性骨髓衰竭和 癌症易感性很强。许多研究都将FA基因突变与家族性乳房联系起来， 胰腺癌和其他癌症，也为FA沉默提供了充分的证据 散发性癌症病因学中的基因。FA细胞对辐射和其他DNA高度敏感 损害剂，特别是DNA交联剂和活性醛，容易产生DNA 复制应激，并表现出染色体脆性。这些表型表现源于 DNA损伤信号和修复的缺陷，以及FA蛋白的功能和物理相互作用 表明与家族性乳腺癌蛋白BRCA1和BRCA2有重要联系。这个 依赖FA/BRCA的DNA损伤反应参与肿瘤抑制 需要了解这一基因组维持途径的机制基础。 在这个项目中，我们将使用生物化学和体内方法相结合的方法来测试新的 关于FA途径协调预防和解决遗传毒性结构的假设 由异常转录事件和HR引起。目标1将重点放在 ID2复合体和含UAF1的复合体与含有核酸的结构结合并激活 人力资源。目标2将探索FANCM-BLM轴是如何分解含有致病RNA和其他 核酸以一种调节HR活动的方式起中介作用。这个项目的成功之处在于 由Patrick Sung博士领导的两个耶鲁大学参与小组的互补专业知识保证 和Gary Kupfer博士，以及更广泛的耶鲁大学内部异常强大的协作框架 社区。此外，私人侦查员还聘请了两名调查人员，克劳迪娅·威斯博士和安德烈斯博士。 阿奎莱拉，他的专业知识将更优雅地让团队审问这一新颖的领域 基因组不稳定。这些属性有助于确保具有最大可能影响的调查结果 获得。由于FA生物学一般与癌症生物学交叉，我们的项目承诺 阐明基因组监测的关键过程以及肿瘤发生的共同主题。 我们希望我们的研究能够深入了解癌症的常见途径，并确定新的靶点。 用于癌症治疗中的操纵。

Project Summary Proteins from the Fanconi anemia (FA) pathway play an integral role in DNA repair by homologous recombination (HR). FA is a multigenic disorder marked by progressive bone marrow failure and a strong cancer predisposition. Numerous studies have linked mutations in FA genes to familial breast, pancreatic, and other cancers, and have also provided ample evidence to implicate silencing of FA genes in the etiology of sporadic cancers. FA cells are hypersensitive to radiation and other DNA damaging agents, DNA crosslinking chemicals and reactive aldehydes in particular, prone to DNA replicative stress, and exhibit chromosome fragility. These phenotypic manifestations stem from defects in DNA damage signaling and repair, and FA protein functional and physical interactions have indicated an important link to the familial breast cancer proteins BRCA1 and BRCA2. The involvement of the FA/BRCA-dependent DNA damage response in cancer suppression underscores the need to understand the mechanistic underpinnings of this genome maintenance pathway. In this project, we will employ a combination of biochemical and in vivo approaches to test the novel hypotheses that the FA pathway coordinates the prevention and resolution of genotoxic structures resulting from aberrant transcription events and HR. Aim 1 will focus on the mechanism whereby the ID2 complex and UAF1-containing complexes engage nucleic acid containing structures and activate HR. Aim 2 will explore how the FANCM-BLM axis resolves pathogenic RNA containing and other nucleic acid intermediates in a way that regulates HR activities. The success of this project is assured by the complementary expertise of the two participating Yale groups, led by Dr Patrick Sung and Dr Gary Kupfer, and an exceptionally strong collaborative framework within the broader Yale community. In addition, the PIs have enlisted two investigators, Dr. Claudia Wiese and Dr. Andres Aguilera, whose expertise will even more elegantly allow the team to interrogate this novel area of genomic instability. These attributes help ensure that findings of the highest possible impact will be obtained. Since the biology of FA intersects with cancer biology in general, our project promises to shed light on critical processes of genomic surveillance as well as common themes of oncogenesis. We expect our studies to yield insight into common pathways of cancer and to identify novel targets for manipulation in cancer therapy.