Investigating the role of HNRPUL1 in regulating the ATR-dependent DNA damage response

所有细胞都有能力处理因暴露于辐射而造成的潜在致命的DNA损伤。这种细胞过程有助于防止突变遗传，需要一种叫做ATR的蛋白质。ATR对受损DNA的反应是阻止其复制。ATR基因的突变，或帮助ATR基因在DNA损伤产生后开启的基因，可导致患有严重发育缺陷的男性出现疾病（如塞克尔综合征、原发性小头畸形和原发性侏儒症）。因此，了解ATR如何识别DNA损伤并阻止细胞生长，以便有时间修复损伤，对于了解这一过程中的缺陷如何导致人类疾病至关重要。我们的实验室最近发现了一种叫做HNRPUL1的蛋白质，我们已经证明，ATR需要它来对某些形式的DNA损伤做出适当的反应。人们对HNRPUL1在细胞中的作用知之甚少。因此，我们的研究目的是研究HNRPUL1如何参与帮助ATR功能。这将通过以下几种方式实现：1)。HNRPUL1是否通过帮助ATR蛋白与受损DNA结合来帮助它被激活？2）. 一旦ATR识别出DNA损伤，HNRPUL1是否会帮助ATR激活所需的其他蛋白质与ATR结合？3）. HNRPUL1能帮助细胞修复DNA损伤吗？和4)。HNRPUL1如何帮助ATR停止细胞生长，从而有时间修复受损的DNA ？回答这些问题将增加我们对细胞对DNA损伤反应的理解，并可能揭示HNRPUL1基因在人类疾病发展中的作用。

All cells have the ability to deal with potentially lethal DNA damage caused by exposure to radiation. This cellular process helps prevent mutations being inherited and requires a protein called ATR. ATR reacts to damaged DNA by stopping it from replicating. Mutations in the ATR gene, or genes that help ATR to become switched on following the generation of DNA damage can cause disorders in man with severe developmental defects (e.g. Seckel syndrome, primary microcephaly and primordial dwarfism). Therefore, understanding how ATR recognises DNA damage and stops cell growth to allow time for the damage to be repaired is essential to understand how defects in this process contribute to human disease. Our laboratory has recently identified a protein called HNRPUL1 that we have shown is required for ATR to respond properly to some forms of DNA damage. Very little is known about the role of HNRPUL1 in the cell. Therefore, our research aim is to investigate how HNRPUL1 is involved in helping ATR function. This will be carried out in a number of ways: 1). Does HNRPUL1 help the ATR protein to be activated by helping it to bind to damaged DNA? 2). Does HNRPUL1 help other proteins, required for ATR activation, bind to ATR once it has recognised DNA damage? 3). Does HNRPUL1 help cells repair DNA damage? and 4). How does HNRPUL1 help ATR to stop cell growth to allow time for the damaged DNA to be repaired? Answering these questions will increase our understanding of the cellular response to DNA damage and may reveal the involvement of the HNRPUL1 gene in the development of human disease.