Uncovering function and mode of activation of the central Fanconi Anemia FANCD2/FANCI DNA repair protein complex, a potential cancer drug target.

人类基因组包含数以千计的基因，这些基因的活动对正常健康的人体非常重要。我们的有机体是由数十亿个细胞组成的，所有这些细胞都来自一个细胞。这是可能的，因为原始细胞分裂成两个细胞，随后产生四个细胞，依此类推。在每一次分裂过程中，准确复制整个基因组是至关重要的。基因组经常受到来自细胞内外的各种来源的破坏。如果细胞不能保持完整的基因组，就会出现突变，这可能会导致一些严重的疾病，比如癌症。为了对抗损伤的影响，我们的细胞进化出了复杂的机制来保护DNA，即所谓的DNA修复途径。这些途径保护基因组，防止有害突变的产生。当这些途径中的一个不能正常工作时，它允许突变不受阻碍地出现。一个特别严重的例子是当Fanconi贫血DNA修复途径不起作用时。当这种情况发生时，它会导致范科尼贫血(FA)。FA是一种遗传性疾病，其特征是患者存在各种发育缺陷和癌症易感性。许多患者无法活到十几岁，这突显了这种疾病的严重性。到目前为止，已经鉴定出18种FA蛋白，其中包括在乳腺癌中发生突变的BRCA1和BRCA2基因。这些蛋白质共同组成FA途径，负责修复DNA交联链，这是一种危险的DNA损伤类型。相应的18个基因中的任何一个突变都会导致FA。与此同时，由于这些DNA交联物是如此危险，导致这种交联物的药物被用于临床治疗非FA癌症患者的癌症。然而，患者往往对这些原本如此成功的药物产生抗药性。据信，这种耐药性是由于癌细胞修复DNA交联链的能力增强所致。如果我们能够阻止癌细胞修复交联链，我们就可以治疗这些致命的癌症，并治愈患者。这项提议的目的是更多地了解癌细胞如何修复DNA交叉连接，以便我们可以利用这些信息来设计可以治疗目前无法治愈的癌症患者的药物。更具体地说，我们将研究一种名为FANCD2/FANCI复合体的蛋白质复合体。这种复合体是细胞修复DNA交联链的中心和绝对关键。我们最近发现了这个复合体的一个新的结构域或部分，这是其功能的基础。我们将利用这一独特的发现来进一步了解FANCD2/FANCI复合体是如何控制DNA交联链修复的。认识的增加反过来将为新型抗癌药物的开发铺平道路。

The human genome contains thousands of genes, activities of which are important for a functioning healthy human body. Our organism is made up of billions of cells, all originating from one single cell. This is possible, since that original cell divided into two cells, which subsequently produced four cells, and so on. It is of crucial importance that the entire genome is duplicated accurately during each division. The genome is constantly subjected to damage from a variety of sources from inside or outside the cell. If cells fail to maintain an intact genome,, mutations can arise, which can cause a number of severe diseases, such as cancer. To counter-act the effects of damage, our cells have evolved sophisticated mechanisms to protect DNA, so called DNA repair pathways. These pathways safeguard the genome to prevent harmful mutations from arising. When one of these pathways fails to function properly, it allows for mutations to arise unhindered. One particularly serious example of this is when the Fanconi Anemia DNA repair pathway is not operational. When that happens, it causes the disease Fanconi Anemia (FA). FA is a genetic disease characterized by various developmental defects and predisposition to cancer in patients. Many patients do not survive beyond their teenage years, underscoring the seriousness of the disease. So far, 18 FA proteins have been identified, which includes the BRCA1 and BRCA2 genes, which are mutated in breast cancer. Together, these proteins compose the FA pathway, which is responsible for repairing DNA crosslinks, a dangerous type of DNA damage. Mutation in any of the corresponding 18 genes can cause FA. At the same time, since these DNA crosslinks are so dangerous, drugs causing such crosslinks are used in the clinic to treat cancer in non-FA cancer patients. However, patients often develop resistance to these otherwise so successful drugs. It is believed that resistance is caused by an increased ability of the cancer cells to repair DNA crosslinks. If we could prevent the cancer cells from repairing the crosslinks, we could treat these deadly cancers and cure the patients. The aim of this proposal is to learn more about how cancer cells repair DNA crosslinks, so that we can use this information to design drugs that can treat patients with currently untreatable cancers. More specifically, we will study a protein complex called the FANCD2/FANCI complex. This complex is central and absolutely critical for cells to repair DNA crosslinks. We have recently discovered a novel domain, or part, of this complex, which is fundamental to its function. We are going to make use of this unique discovery to further our understanding of how the FANCD2/FANCI complex controls DNA crosslink repair. The increased understanding will in turn pave the way for the development of novel cancer drugs.