The structure and function of the SLX4 nuclease complex

我们的基因蓝图包含在细胞核中长长的染色体DNA分子中。在我们的一生中，我们许多组织中的细胞都在不断地分裂，以替换旧的和受损的细胞。这是自然衰老过程的一部分。在分裂之前，细胞必须准确地复制其DNA，以防止染色体发生变化，这些变化可能导致使人衰弱的退行性疾病，包括癌症和神经退行性疾病，其中许多都是衰老的标志。DNA复制是由DNA聚合酶完成的，它复制亲本细胞中的模板链，作为完整染色体复制和细胞分裂的一部分。由于DNA是由两条DNA链组成的，复制涉及到这两条DNA链的分离和复制，每条DNA链的复制在一个协调的过程中需要每条DNA链的专用因子。当DNA链分离时，产生的结构包含解绕区域，解绕和复制进行的连接处被称为“复制叉”。重要的是，在每一轮复制过程中，专用复制蛋白都会遇到DNA内阻碍其进展的结构或损伤。这些结构可能是DNA中自然产生的“难以”复制的区域，或者它们可能是DNA中化学损伤的区域。这种化学损害可能是由于不断发生的正常细胞过程而自发产生的，也可能是由于暴露于外部因素，例如太阳辐射（阳光）或各种环境化学因素造成的。此外，用于治疗癌症的几种重要药物也会产生这种类型的损伤，充分了解细胞对这种损伤的反应可能有助于我们改善化疗。在复制过程中遇到的异常必须被修复，这通常涉及到一种叫做核酸内切酶的蛋白质，它可以切割异常的DNA结构。这可能发生在复制过程中，也可能发生在DNA复制过程中产生的结构在复制完成后被分解。内切酶启动这种级联修复事件，已知的几个关键因子是XPF-ERCC1， SLX1和MUS81-EME1蛋白。然而，最近发现，这些因子一定与一种叫做SLX4的大型“平台”蛋白有关，这种蛋白有助于将其导向受损的复制叉，以及与受损DNA修复相关的其他结构。高分辨率地求解SLX4配合物的三维结构将是理解其机制的关键。反过来，这最终将有助于开发新的治疗方法，以对抗与衰老有关的一些退行性疾病。它还应该提高我们对发育和恶性疾病的诊断，并提供重要的见解，制药和生物技术部门可以利用它来产生新的药物和技术，特别是因为似乎有针对性地抑制这些修复反应可能有助于改善癌症治疗。

Our genetic blueprint is contained within long, chromosomal molecules of DNA in the nucleus of our cells. During our lifetime, the cells in many of our tissues are constantly dividing to replace old and damaged cells. This is part of the natural ageing process. Before dividing, a cell must replicate its DNA accurately to prevent chromosomal changes that could lead to debilitating degenerative diseases including cancer and neurodegeneration, many of which are hallmarks of ageing. DNA replication is performed by DNA polymerases that copy the template strands in the parent cell, as part of full chromosome duplication and cell division. Since the DNA is composed of two strands of DNA, replication involves separation and replication of these two strands, and replication of each strand in a co-ordinated process requiring dedicated factors for each strand. When the DNA strands are separated the structure produced contains unwound regions, and the junction where unwinding and replication are ongoing is named a 'replication fork'. Importantly, during every round of replication the dedicated replication proteins encounter structures or damage within the DNA that block their progress. These structures might be naturally arising regions of the DNA that are 'hard' to replicate, or they might be chemically damaged regions within DNA. Such chemical damage can arise spontaneously as a result of normal cellular processes that are constantly occurring, or they might be inflicted through exposure to external agents, for example solar radiation (sunlight) or a variety of environmental chemical agents. Moreover, this type of damage is produced is also produced by several important medicines used to treat cancer, and a full understanding of how cells respond to this damage might help us improve chemotherapy.The abnormalities encountered during replication must be repaired, and this frequently involves proteins called endonucleases, that cut abnormal DNA structures. This can occur either during the process of replication, or structures generated during DNA replication can be later resolved after replication is complete. Endonucleases initiate this cascade of repair events, and several key factors known to be required for are the XPF-ERCC1, SLX1 and MUS81-EME1 proteins. However, it has recently become apparent that these factors must be associated with a large 'platform' protein called SLX4 which helps direct it to the damaged replication forks, and other structures associated with the repair of damaged DNA. Solving the three-dimensional structure of the SLX4 complex at high resolution will be key to understanding its mechanism. This in turn will ultimately help in the development of new therapeutics combating a number of degenerative conditions associated with ageing. It should also improve our diagnosis of developmental and malignant disorders and provide important insights that the pharmaceutical and biotechnology sectors could use to generate new medicines and technologies, especially since it appears that targeted inhibition of these repair reactions might help improve cancer therapy.