Fanconi anemia pathway in DNA damage repair

描述(申请人提供)：Fanconi贫血(FA)是一种罕见的遗传疾病，其特征是发育异常、进行性再生障碍性贫血和癌症发病率增加。虽然FA途径被认为参与了DNA修复，但该途径在DNA修复中的确切作用仍有待阐明。FA途径的关键功能是促进DNA损伤后FANCD2的单素化。然而，FANCD2是如何被招募到DNA损伤部位的还不清楚。更重要的是，FANCD2单素化在DNA修复中的任务仍然是一个谜。我们最近有了两个发现，这可能会回答上面提到的问题。首先，当我们研究新发现的DNA修复中的SOSS复合体时，我们发现这些复合体还与FANCI和FANCD2有关。此外，我们还表明，在DNA损伤后，SOSS复合体对于FANCI和FANCD2的有效染色质负载、焦点形成和单素化是必需的。这些研究表明，SOSS复合体与FA核心复合体共同作用，参与DNA损伤后FANCI/FANCD2泛素化的调节。其次，我们发现泛素结合锌指(UBZ)结构域核酸酶KIAA1018/FAN1与FANCD2相互作用。我们随后的研究表明，该蛋白作用于FANCD2下游，并参与DNA修复。我们认为该蛋白将FA途径与DNA损伤修复联系起来。此外，我们还在研究另一种新发现的FA蛋白SLX4/FANCP，它可能与KIAA1018/FAN1一起作用于DNA修复。基于这些激动人心的初步研究，我们建议：1)通过它们与SOSS复合体的结合来确定FANCI/FANCD2的定位调节；2)确定KIAA1018/FAN1和SLX4/FANCP在DNA修复中的功能意义；3)确定KIAA1018/FAN1在维持基因组稳定和抑制肿瘤方面的体内功能。 公共卫生相关性：Fanconi贫血(FA)是一种罕见的遗传性疾病，以骨髓衰竭、发育异常和高恶性肿瘤发病率为特征。FA通路中至少有15个基因参与DNA损伤修复，然而，FA通路中最关键的事件是FANCD2的单素化。进一步研究FANCD2单泛素化的调控和功能将揭示细胞如何在DNA损伤后促进生存和确保基因组稳定，这对于了解放射和化疗药物治疗癌症的疗效至关重要。

DESCRIPTION (provided by applicant): Fanconi anemia (FA) is a rare genetic disorder characterized by developmental abnormalities, progressive aplastic anemia, and increased cancer incidence. Although FA pathway is believed to participate in DNA repair, the exact role of this pathway in DNA repair remains to be elucidated. The key function of the FA pathway is to promote FANCD2 monoubiquitination following DNA damage. However, how FANCD2 is recruited to sites of DNA damage is unknown. More importantly, the task of FANCD2 monoubiquitination in DNA repair is still a mystery. We made two discoveries recently, which will likely answer the questions mentioned above. First, when we were studying the newly identified SOSS complexes in DNA repair, we found that these complexes also associated with FANCI and FANCD2. Moreover, we showed that SOSS complexes are required for the efficient chromatin loading, focus formation, and monoubiquitination of FANCI and FANCD2 following DNA damage. These studies suggest that SOSS complexes act together with the FA core complex and participate in the regulation of FANCI/FANCD2 ubiquitination following DNA damage. Second, we discovered that an ubiquitin-binding zinc finger (UBZ) domain-containing nuclease KIAA1018/FAN1 interacted with FANCD2. Our subsequent studies suggested that this protein acts downstream of FANCD2 and participates in DNA repair. We propose that this protein links the FA pathway to DNA damage repair. Moreover, we are also studying another newly identified FA protein SLX4/FANCP, which may act with KIAA1018/FAN1 in DNA repair. Based on these exciting preliminary studies, we propose to: 1) Define the regulation of FANCI/FANCD2 localization via their associations with SOSS complexes; 2) Determine the functional significance of KIAA1018/FAN1 and SLX4/FANCP in DNA repair; 3) Identify the in vivo functions of KIAA1018/FAN1 in the maintenance of genomic stability and tumor suppression. PUBLIC HEALTH RELEVANCE: Fanconi anemia (FA) is a rare genetic disorder characterized by bone marrow failure, developmental abnormalities and high incidence of malignancies. There are at least 15 genes involved in the FA pathway, which are believed to function in DNA damage repair; however, the most critical event in the FA pathway is monoubiquitination of FANCD2. Further study of the regulation and function of FANCD2 monoubiquitination will reveal how cells promote survival and ensure genomic stability following DNA damage, which are critically important for understanding the efficacy of cancer treatments with radiation and chemotherapeutic agents.