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

doi:10.1016/j.celrep.2021.109153

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 journal › Article › peer-review

26 Citations (Scopus)

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 language	English
Article number	109153
Journal	Cell Reports
Volume	35
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2021.109153
Publication status	Published - May 25 2021
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2021 The Author(s)

ASJC Scopus Subject Areas

General Biochemistry,Genetics and Molecular Biology

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.celrep.2021.109153

Cite this

Kilgas, S., Singh, A. N., Paillas, S., Then, C. K., Torrecilla, I., Nicholson, J., Browning, L., Vendrell, I., Konietzny, R., Kessler, B. M., Kiltie, A. E., & Ramadan, K. (2021). p97/VCP inhibition causes excessive MRE11-dependent DNA end resection promoting cell killing after ionizing radiation. Cell Reports, 35(8), Article 109153. https://doi.org/10.1016/j.celrep.2021.109153

@article{1eea856f2de74f859475d9f6fcec6a51,

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

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

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

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = may,

day = "25",

doi = "10.1016/j.celrep.2021.109153",

language = "English",

volume = "35",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "8",

}

TY - JOUR

T1 - p97/VCP inhibition causes excessive MRE11-dependent DNA end resection promoting cell killing after ionizing radiation

AU - Kilgas, Susan

AU - Singh, Abhay Narayan

AU - Paillas, Salome

AU - Then, Chee Kin

AU - Torrecilla, Ignacio

AU - Nicholson, Judith

AU - Browning, Lisa

AU - Vendrell, Iolanda

AU - Konietzny, Rebecca

AU - Kessler, Benedikt M.

AU - Kiltie, Anne E.

AU - Ramadan, Kristijan

PY - 2021/5/25

Y1 - 2021/5/25

N2 - 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.

AB - 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.

KW - bladder cancer

KW - CB-5083

KW - DNA damage

KW - DNA double-strand break repair

KW - homologous recombination

KW - ionizing radiation

KW - IR

KW - MRE11

KW - p97

KW - single-strand annealing

UR - http://www.scopus.com/inward/record.url?scp=85106522028&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85106522028&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2021.109153

DO - 10.1016/j.celrep.2021.109153

M3 - Article

C2 - 34038735

AN - SCOPUS:85106522028

SN - 2211-1247

VL - 35

JO - Cell Reports

JF - Cell Reports

IS - 8

M1 - 109153

ER -

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

Abstract

Bibliographical note

ASJC Scopus Subject Areas

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this