Fanconi anemia pathway in DNA damage repair

描述（由申请人提供）：范可尼贫血（FA）是一种罕见的遗传性疾病，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通路被认为参与DNA修复，但该通路在DNA修复中的确切作用仍有待阐明。FA途径的关键功能是在DNA损伤后促进FANCD 2单泛素化。然而，FANCD 2如何被募集到DNA损伤位点尚不清楚。更重要的是，FANCD 2单泛素化在DNA修复中的任务仍然是一个谜。 我们最近有两个发现，可能会回答上面提到的问题。首先，当我们在研究DNA修复中新发现的SOSS复合物时，我们发现这些复合物也与FANCI和FANCD 2相关。此外，我们发现SOSS复合物是DNA损伤后FANCI和FANCD 2的有效染色质加载、焦点形成和单泛素化所必需的。这些研究表明，SOSS复合物与FA核心复合物一起作用，并参与DNA损伤后FANCI/FANCD 2泛素化的调节。其次，我们发现了一种含有泛素结合锌指（UBZ）结构域的核酸酶KIAA 1018/FAN 1与FANCD 2相互作用。我们随后的研究表明，这种蛋白质作用于FANCD 2的下游，并参与DNA修复。我们认为这种蛋白质将FA途径与DNA损伤修复联系起来。此外，我们还研究了另一个新发现的FA蛋白SLX 4/FANCP，它可能与KIAA 1018/FAN 1一起参与DNA修复。 基于这些令人兴奋的初步研究，我们提出：1）通过与SOSS复合物的关联来定义FANCI/FANCD 2定位的调节; 2）确定KIAA 1018/FAN 1和SLX 4/FANCP在DNA修复中的功能意义; 3）确定KIAA 1018/FAN 1在维持基因组稳定性和肿瘤抑制中的体内功能。

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.