Mechanistic Dissection of the Fanconi Anemia Pathway of DNA Damage Response and R

描述（由申请人提供）：范可尼贫血（FA）是一种多基因疾病，以进行性骨髓衰竭和强烈的癌症易感性为特征。大量研究已经将FA基因突变与家族性乳腺癌、胰腺癌和其他癌症联系起来，并且也提供了充分的证据表明FA基因沉默与散发性癌症的病因有关。FA细胞对辐射和其他DNA损伤剂（尤其是DNA交联化学物质）高度敏感，容易受到DNA复制应激的影响，并表现出染色体脆弱性。这些表型表现源于DNA损伤信号传导和修复缺陷，FA蛋白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。FA/ brca依赖性DNA损伤反应在癌症抑制中的参与强调了了解这种基因组维持途径的机制基础的必要性。在这个项目中，我们将采用生物化学和体内方法相结合的方法来检验关于蛋白质-蛋白质和蛋白质-DNA相互作用的假设，这些相互作用涉及关键FA和伴侣蛋白，介导了fansi - fancd2复合物的翻译后修饰以及同源定向修复受损DNA的方式。这个项目的成功得益于由Patrick Sung博士和Gary Kupfer博士领导的耶鲁大学两个参与小组的互补专业知识，以及耶鲁大学更广泛社区内异常强大的合作框架。这些属性有助于确保获得可能产生最大影响的发现。由于FA生物学通常与癌症生物学交叉，我们的项目有望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，并确定癌症治疗中操纵的新靶点。

DESCRIPTION (provided by applicant): Fanconi anemia (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 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 breas 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 hypotheses regarding the manner by which protein-protein and protein-DNA interactions involving key FA and partner proteins mediate the post-translational modifications of the FANCI-FANCD2 complex and also the homology-directed repair of damaged DNA. 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. 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.