Journal
CELL REPORTS
Volume 35, Issue 8, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2021.109153
Keywords
-
Categories
Funding
- Cancer Research UK (CRUK) [C5255/A23755]
- Medical Research Council UK (MRC) program grant [MC_PC 12001/1 (MC_UU_00001/1)]
- Breast Cancer Now [2019DecPR1406]
- MRC Oxford Institute of Radiation Oncology (OIRO) CRUK studentship
Ask authors/readers for more resources
The ATPase p97 interacts with the MRN complex on chromatin and inactivation of p97 affects DNA repair and radiosensitivity. Inhibition of p97 function increases tumor cell killing following ionizing radiation by promoting MRE11 nuclease accumulation, suggesting potential use of p97 inhibitors in radiotherapy patients.
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 CB5083 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available