Investigating how cells repair DNA damage during mitosis

DNA损伤对细胞分裂过程中适当的染色体分离构成严重威胁，如果修复不当，可能会导致细胞死亡或癌症。矛盾的是，在有丝分裂期间，分裂细胞关闭了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，因为包括放射治疗和一些化疗药物在内的许多癌症治疗方法都会导致DNA损伤，从而在有丝分裂期间杀死癌细胞。该项目旨在加深我们对控制DNA修复途径的调控机制的理解。鉴于DNA修复缺陷会导致多种健康影响，包括免疫缺陷、神经退化和过早衰老(例如，在我们最近的报告Balmus等人，基因开发。2016)。因此，该项目属于“神经退行性变、痴呆症和精神健康”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可能性，该项目也坚定地归入“精确医学”MRC健康焦点主题。我们最近发现了一种新的蛋白质复合体，在有丝分裂期间细胞对DNA损伤的反应中具有特定的作用。这种复合体标记DNA断裂，并形成蛋白质细丝，连接DNA断裂的两个末端。然而，我们仍然不知道这种蛋白质复合体是如何形成的，它是如何调节的，以及对缺乏它的生物体会产生什么后果。DPhil项目的目的是解决这些问题，并在这样做的同时，为一种新的基本生化途径提供新的见解，该途径可能被作为一种新的抗癌疗法。

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.