DNA damage responses in mammalian cells and their contribution to human health disorders

DNA损伤反应包括DNA修复过程和信号转导机制。该基金的重点是对DNA双链断裂（DSB）的反应，这是一种重要的致命和致癌病变。DSB由内源性氧化损伤引起，在某些代谢过程中，包括V（D）J重组，免疫发育过程中的一个步骤，以及暴露于电离辐射后。DNA非同源末端连接（NHEJ）和同源重组（HR）代表DSB修复途径，共济失调毛细血管扩张突变（ATM）调节主要的DSB信号转导反应。该计划旨在了解NHEJ如何处理和重新加入DSB及其对人类疾病的贡献。已知三种由NHEJ缺陷引起的疾病，它们都与免疫缺陷和放射敏感性有关。ATM信令对于大多数DSB修复是无效的。然而，DSB的一个子集需要ATM信号蛋白和核酸酶Artemis。我们将研究Artemis和ATM在DSB修复中的作用。ATR调节相关的信号传导过程，该过程由停滞的复制叉和大体积病变激活。Seckel综合征的特征在于ATR信号通路中的缺陷，尽管并非所有缺陷基因都已被鉴定。该计划还旨在深入了解ATR信号及其对影响人类健康的疾病的贡献。

DNA damage responses encompass DNA repair processes and signal transduction mechanisms. The grant focuses on the response to DNA double strand breaks (DSBs), an important lethal and carcinogenic lesion. DSBs arise from endogenous oxidative damage, during certain metabolic processes including V(D)J recombination, a step during immune development, and following exposure to ionising radiation. DNA non-homologous end-joining (NHEJ) and homologous recombination (HR) represent DSB repair pathways and Ataxia telangiectasia mutated (ATM) regulates the major DSB signalling response. This programme aims to understand how DSBs are processed and rejoined by NHEJ and its contribution to human disease. Three disorders conferred by defects in NHEJ have known and all are associated with immunodeficiency and radiosensitivity. ATM signalling is dispensable for most DSB repair. However, a subset of DSBs require ATM signalling proteins and a nuclease, Artemis. We will examine the roles of Artemis and ATM in DSB repair. ATR regulates a related signalling process that is activated by stalled replication forks and bulky lesions. Seckel Syndrome is characterised by defects in the ATR signalling pathway, although not all defective genes have been identified. This programme will also aim to gain insight into ATR signalling and its contribution to disorders affecting human health.