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Targeting OGG1 arrests cancer cell proliferation by inducing replication stress

Visnes, Torkild ; Benítez-Buelga, Carlos ; Cázares-Körner, Armando ; Sanjiv, Kumar ; Hanna, Bishoy M F ; Mortusewicz, Oliver ; Rajagopal, Varshni ; Albers, Julian J ; Hagey, Daniel W and Bekkhus, Tove , et al. (2020) In Nucleic Acids Research
Abstract

Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of... (More)

Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nucleic Acids Research
article number
gkaa1048
publisher
Oxford University Press
external identifiers
  • pmid:33211885
ISSN
1362-4962
DOI
10.1093/nar/gkaa1048
language
English
LU publication?
yes
additional info
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.
id
837000b6-c1b2-4a36-b001-e734c2c356eb
date added to LUP
2020-11-22 15:49:47
date last changed
2020-11-27 14:46:51
@article{837000b6-c1b2-4a36-b001-e734c2c356eb,
  abstract     = {<p>Altered oncogene expression in cancer cells causes loss of redox homeostasis resulting in oxidative DNA damage, e.g. 8-oxoguanine (8-oxoG), repaired by base excision repair (BER). PARP1 coordinates BER and relies on the upstream 8-oxoguanine-DNA glycosylase (OGG1) to recognise and excise 8-oxoG. Here we hypothesize that OGG1 may represent an attractive target to exploit reactive oxygen species (ROS) elevation in cancer. Although OGG1 depletion is well tolerated in non-transformed cells, we report here that OGG1 depletion obstructs A3 T-cell lymphoblastic acute leukemia growth in vitro and in vivo, validating OGG1 as a potential anti-cancer target. In line with this hypothesis, we show that OGG1 inhibitors (OGG1i) target a wide range of cancer cells, with a favourable therapeutic index compared to non-transformed cells. Mechanistically, OGG1i and shRNA depletion cause S-phase DNA damage, replication stress and proliferation arrest or cell death, representing a novel mechanistic approach to target cancer. This study adds OGG1 to the list of BER factors, e.g. PARP1, as potential targets for cancer treatment.</p>},
  author       = {Visnes, Torkild and Benítez-Buelga, Carlos and Cázares-Körner, Armando and Sanjiv, Kumar and Hanna, Bishoy M F and Mortusewicz, Oliver and Rajagopal, Varshni and Albers, Julian J and Hagey, Daniel W and Bekkhus, Tove and Eshtad, Saeed and Baquero, Juan Miguel and Masuyer, Geoffrey and Wallner, Olov and Müller, Sarah and Pham, Therese and Göktürk, Camilla and Rasti, Azita and Suman, Sharda and Torres-Ruiz, Raúl and Sarno, Antonio and Wiita, Elisée and Homan, Evert J and Karsten, Stella and Marimuthu, Karthick and Michel, Maurice and Koolmeister, Tobias and Scobie, Martin and Loseva, Olga and Almlöf, Ingrid and Unterlass, Judith Edda and Pettke, Aleksandra and Boström, Johan and Pandey, Monica and Gad, Helge and Herr, Patrick and Jemth, Ann-Sofie and El Andaloussi, Samir and Kalderén, Christina and Rodriguez-Perales, Sandra and Benítez, Javier and Krokan, Hans E and Altun, Mikael and Stenmark, Pål and Berglund, Ulrika Warpman and Helleday, Thomas},
  issn         = {1362-4962},
  language     = {eng},
  publisher    = {Oxford University Press},
  series       = {Nucleic Acids Research},
  title        = {Targeting OGG1 arrests cancer cell proliferation by inducing replication stress},
  url          = {http://dx.doi.org/10.1093/nar/gkaa1048},
  doi          = {10.1093/nar/gkaa1048},
  year         = {2020},
}