Completed Genetics & Molecular Biology Cells, Biochemistry & Physiology

Post-Translational Modifications in the Radiation Damage Response

Funder MRC (part of UKRI)
Recipient organisation
Funding £2.5M
Period Mar 2017 — Mar 2022

In plain English

AI plain-English summary

A protein disposal system inside cells helps determine whether damaged DNA gets repaired or triggers cancer—and researchers now aim to prove that blocking this system could make chemotherapy more effective. The problem is that cancer cells divide rapidly and accumulate DNA damage, yet many survive and become resistant to treatment. The protein complex p97, guided by its cofactors, decides which damaged proteins to remove during DNA replication and repair. When these cofactors mutate, genome instability rises, leading to premature aging and cancer. Scientists understand that p97 is essential, but they do not know exactly which cofactors control its role in DNA repair—and therefore cannot yet target it safely. If this project succeeds, it will establish a new concept: that many cancers depend on the p97 system for survival and chemoresistance. That would open the door to developing p97 system inhibitors as a new class of cancer drugs. Because cancer cells rely more heavily on this system than healthy cells, such inhibitors could selectively kill tumours while sparing normal tissue. This is primarily fundamental science—uncovering the molecular mechanics of a critical cellular machine—but with a clear path toward therapeutic application.

View original technical description
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.

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Researchers

Kristijan Ramadan (Principal Investigator)

Related Research

Grants with similar aims, by meaning.

The p97/VCP system in Ionising Radiation Response
Molecular insights into ubiquitin remodelling factor p97(VCP) in DNA damage response and genome stability
Understanding the role of PARPs in replication-associated DNA damage repair.
Determining a role of USP7 in controlling DNA repair pathways as a possible therapeutic target
Structures, Recruitment and Regulation of Key Components in DNA Damage Response

Original classification

Intramural

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