Investigating how cells repair DNA damage during mitosis

DNA损伤对细胞分裂过程中染色体的正确分离构成严重威胁，如果修复不当，可能导致细胞死亡或癌症。奇怪的是，在有丝分裂期间，分裂细胞关闭DNA修复途径，直到它们的子细胞重新进入间期。因此，细胞如何处理有丝分裂过程中发生的DNA损伤仍不清楚，但这是基础癌细胞生物学中的一个关键问题，因为许多癌症治疗，包括放射治疗和一些化疗药物，都会导致DNA损伤，从而在有丝分裂过程中杀死癌细胞。本项目旨在加深我们对控制DNA修复途径的调节机制的理解。鉴于DNA修复缺陷导致各种健康影响，包括免疫缺陷、神经变性和过早衰老（如例如在我们最近的报告Balmus等人，Genes Dev. 2016）。因此，该项目福尔斯“神经变性，痴呆症和心理健康”MRC优先挑战。鉴于PARP抑制剂在靶向某些DNA修复缺陷癌症方面的成功，以及DNA修复途径之间进一步合成致命关系的潜力，该项目也坚定福尔斯“精准医学”MRC健康焦点主题。我们最近发现了一种新型蛋白质复合物，在有丝分裂期间对DNA损伤的细胞反应中具有特定作用。这种复合物标记DNA断裂并形成蛋白质丝，可以桥接两个断裂的DNA末端。然而，我们仍然不知道这种蛋白质复合物是如何形成的，它是如何调节的，以及缺乏它的生物体的后果是什么。这个博士项目的目的是解决这些问题，并在这样做的过程中，提供新的见解到一个新的基本生化途径，可以作为一种新的抗癌疗法的目标。

DNA damage poses a serious threat to proper chromosome segregation during cell division, and if repaired incorrectly can cause cell death or cancer. Paradoxically, during mitosis, dividing cells switch off DNA repair pathways until their daughter cells re-enter interphase. Therefore, how cells deal with DNA damage that occurs during mitosis is still unclear, but this is a critical question in basic cancer cell biology because many cancer therapies including radiotherapy and some chemotherapeutic drugs cause DNA damage that kills cancer cells during mitosis.The project aims to develop our understanding of the regulatory mechanisms controlling DNA repair pathways. Given that DNA-repair deficiencies lead to variety of health impacts including immunodeficiency, neurodegeneration and premature aging (as shown e.g. in our recent report Balmus et al., Genes Dev. 2016). The project therefore falls under the "Neurodegeneration, dementia & mental health" MRC Priority Challenge. Given the success of PARP inhibitors in targeting certain DNA repair-deficient cancers and the potential for further synthetic lethal relationships between DNA repair pathways, the project also firmly falls under the "Precision medicine" MRC Health Focus Theme.We recently identified a novel protein complex with a specific role in the cellular response to DNA damage during mitosis. This complex marks DNA breaks and forms protein filaments that can bridge two broken DNA ends. However, we still do not understand how this protein complex forms, how it is regulated, and what the consequences are for organisms that lack it.The aim of this DPhil project is to address these questions and in doing so, provide novel insights into a novel fundamental biochemical pathway that could be targeted as a novel anti-cancer therapy.