Post-Translational Modifications in the Radiation Damage Response

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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.