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

Susan Kilgas, Abhay Narayan Singh, Salome Paillas, Chee Kin Then, Ignacio Torrecilla, Judith Nicholson, Lisa Browning, Iolanda Vendrell, Rebecca Konietzny, Benedikt M. Kessler, Anne E. Kiltie*, Kristijan Ramadan

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number109153
Number of pages25
JournalCell Reports
Volume35
Issue number8
DOIs
Publication statusPublished - 25 May 2021

Keywords

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

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