Post-Translational Modifications in the Radiation Damage Response

DNA复制和DNA修复是基因组扩增和稳定的两个重要过程。这两个过程的缺陷导致基因组不稳定和各种人类疾病，如早衰和癌症。我们最近发现泛素依赖的AAA atp酶p97在DNA复制和DNA修复的调控中起重要作用。p97在DNA复制和DNA修复调控中的特异性是由p97辅助因子决定的。现在，我们的目标是识别和表征参与DNA复制和DNA修复调控的p97系统（p97/VCP +辅因子）。我们目前的研究结果表明，p97辅助因子的突变导致人类癌症和早衰。p97系统的进一步鉴定和表征将有助于我们理解p97辅助因子突变导致癌症的原因。我们将使用生物化学和细胞生物学方法来描述p97系统在DNA复制和修复中的分子机制。考虑到癌细胞比大多数人类细胞分裂得快得多，并且改变了新陈代谢，从而导致DNA损伤升高，p97系统已成为癌症治疗的一个有吸引力的药物靶点。该奖项旨在展示一个新的概念，该概念基于许多癌症的生存和化疗耐药取决于p97系统的假设，并将为鉴定用于癌症治疗的潜在p97系统抑制剂铺平道路。

DNA replication and DNA repair are two essential processes for genome amplification and stability. Defects in these two processes lead to genome instability and various human diseases such as premature aging and cancer. We have recently identified that the ubiquitin dependent AAA ATPase p97 plays an essential role in the regulation of DNA replication and DNA repair. The specificity of p97 in the regulation of DNA replication and DNA repair is governed by p97 cofactors. Now, we aim to identify and characterise the p97 system (p97/VCP + cofactors) involved in the regulation of DNA replication and DNA repair. Our current results demonstrate that mutations in p97 cofactors lead to cancer and premature aging in humans. Further identification and characterisation of the p97 system will help us to understand why mutations in p97 cofactors lead to cancer. We will use biochemical and cell biological approaches to delineate molecular mechanisms of the p97 system in DNA replication and repair. Given that cancer cells divide much faster than the majority of human cells and have altered metabolism, which leads to elevated DNA damage, the p97 system has emerged as an attractive drug target for cancer therapy. This award aims to demonstrate a new concept, which is based on the hypothesis that the survival and chemoresistance of many cancers depends on the p97 system, and will pave the way for identification of potential p97 system inhibitors for cancer therapy.