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

人类基因组包含数千个基因，这些基因的活动对健康的人体功能至关重要。我们的生物体是由数十亿个细胞组成的，所有细胞都起源于一个细胞。这是可能的，因为最初的细胞分裂成两个细胞，随后又产生四个细胞，以此类推。在每次分裂过程中，整个基因组的精确复制是至关重要的。基因组不断受到来自细胞内外各种来源的损害。如果细胞不能保持完整的基因组，就会产生突变，从而导致许多严重的疾病，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。当其中一条途径不能正常发挥作用时，突变就会不受阻碍地出现。一个特别严重的例子是范可尼贫血症的DNA修复途径不工作。当这种情况发生时，它会导致范可尼贫血（FA）。FA是一种以各种发育缺陷和癌症易感性为特征的遗传性疾病。许多患者活不过十几岁，这凸显了这种疾病的严重性。到目前为止，已经确定了18种FA蛋白，其中包括BRCA1和BRCA2基因，这两种基因在乳腺癌中发生突变。这些蛋白质共同构成FA通路，负责修复DNA交联，这是一种危险的DNA损伤。相应的18个基因中的任何一个发生突变都可能导致FA。同时，由于这些DNA交联非常危险，导致这种交联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非常成功的药物产生耐药性。据信，耐药性是由癌细胞修复DNA交联的能力增强引起的。如果我们能阻止癌细胞修复交联，我们就能治疗这些致命的癌症并治愈病人。这项提议的目的是更多地了解癌细胞是如何修复DNA交联的，这样我们就可以利用这些信息来设计药物，治疗目前无法治愈的癌症患者。更具体地说，我们将研究一种叫做FANCD2/FANCI复合物的蛋白质复合物。这个复合体是细胞修复DNA交联的核心和绝对关键。我们最近发现了这个复合体的一个新区域，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复合物如何控制DNA交联修复。进一步的了解将为开发新的抗癌药物铺平道路。

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.