2. Academic Validation
  3. p97/VCP inhibition causes excessive MRE11-dependent DNA end resection promoting cell killing after ionizing radiation

p97/VCP inhibition causes excessive MRE11-dependent DNA end resection promoting cell killing after ionizing radiation

  • Cell Rep. 2021 May 25;35(8):109153. doi: 10.1016/j.celrep.2021.109153.
Susan Kilgas 1,  Abhay Narayan Singh 1,  Salome Paillas 1,  Chee-Kin Then 1,  Ignacio Torrecilla 1,  Judith Nicholson 1,  Lisa Browning 2,  Iolanda Vendrell 3,  Rebecca Konietzny 4,  Benedikt M Kessler 4,  Anne E Kiltie 5,  Kristijan Ramadan 6
Affiliations

Affiliations

  • 1 MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK.
  • 2 Department of Cellular Pathology, Oxford University Hospitals, NHS Foundation Trust, Oxford OX3 9DU, UK.
  • 3 MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK; TDI Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
  • 4 TDI Mass Spectrometry Laboratory, Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.
  • 5 MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK. Electronic address: anne.kiltie@oncology.ox.ac.uk.
  • 6 MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford OX3 7DQ, UK. Electronic address: kristijan.ramadan@oncology.ox.ac.uk.
PMID: 34038735 DOI: 10.1016/j.celrep.2021.109153
Abstract

The ATPase p97 is a central component of the ubiquitin-proteasome degradation system. p97 uses its ATPase activity and co-factors to extract ubiquitinated substrates from different cellular locations, including DNA lesions, thereby regulating DNA repair pathway choice. Here, we find that p97 physically and functionally interacts with the MRE11-RAD50-NBS1 (MRN) complex on chromatin and that inactivation of p97 blocks the disassembly of the MRN complex from the sites of DNA damage upon ionizing radiation (IR). The inhibition of p97 function results in excessive 5'-DNA end resection mediated by MRE11 that leads to defective DNA repair and radiosensitivity. In addition, p97 inhibition by the specific small-molecule inhibitor CB-5083 increases tumor cell killing following IR both in vitro and in vivo. Mechanistically, this is mediated via increased MRE11 Nuclease accumulation. This suggests that p97 inhibitors might be exploited to improve outcomes for radiotherapy patients.

Keywords

CB-5083; DNA damage; DNA double-strand break repair; IR; MRE11; bladder cancer; homologous recombination; ionizing radiation; p97; single-strand annealing.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12861
    99.90%, p97 AAA ATPase/VCP Inhibitor
    p97