The regulation of Mre11-Rad50-Nbs1 (MRN) complex disassembly in response to ionising radiation.

The complex formed by MRE11 -RAD50 and -NBS1, designated the MRN complex, has a well-defined role in homologous recombination, a DNA repair pathway that repairs double-strand breaks (DSBs). There is mechanistic detail regarding how the MRN complex is recruited to the sites of DSBs and how it completes its physiological role although it is not known how the MRN complex is disassembled from DBSs. Recent evidence suggests that the AAA+ ATPase p97 has a role in extracting the MRN complex from chromatin. Without this segregase or unfoldase, MRE11 accumulates on chromatin and genome instability ensues. I aim to understand the mechanistic details of how p97 removes the MRN complex from chromatin.

The MRN complex and p97 are associated with cancer formation and advanced cancers. Furthermore, they have been suggested as cancer therapy targets, as sole therapies or in combination with other therapies, inducing synthetic lethality e.g., radiosensitisers. There are ongoing clinical trials targeting both of these agents (NCT03921021 and NCT04402541).