Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells
Introduction Ataxia telangiectasia mutated and Rad3 Related (ATR) protein kinase is a key sensor of single-stranded DNA associated with stalled replication forks and repair intermediates generated during DNA repair. XRCC1 is a critical enzyme in single strand break repair and base excision repair....
| Main Authors: | , , , , , , , , |
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| Format: | Article |
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Public Library of Science
2013
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| Online Access: | https://eprints.nottingham.ac.uk/2510/ |
| _version_ | 1848790803309133824 |
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| author | Sultana, Rebeka Abdel-Fatah, Tarek Perry, Christina Moseley, Paul Albarakti, Nada Mohan, Vivek Seedhouse, Claire Chan, Stephan Madhusudan, Srinivasan |
| author_facet | Sultana, Rebeka Abdel-Fatah, Tarek Perry, Christina Moseley, Paul Albarakti, Nada Mohan, Vivek Seedhouse, Claire Chan, Stephan Madhusudan, Srinivasan |
| author_sort | Sultana, Rebeka |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | Introduction
Ataxia telangiectasia mutated and Rad3 Related (ATR) protein kinase is a key sensor of single-stranded DNA associated with stalled replication forks and repair intermediates generated during DNA repair. XRCC1 is a critical enzyme in single strand break repair and base excision repair. XRCC1-LIG3 complex is also an important contributor to the ligation step of the nucleotide excision repair response.
Methods
In the current study, we investigated synthetic lethality in XRCC1 deficient and XRCC1 proficient Chinese Hamster ovary (CHO) and human ovarian cancer cells using ATR inhibitors (NU6027). In addition, we also investigated the ability of ATR inhibitors to potentiate cisplatin cytotoxicity in XRCC1 deficient and XRCC1 proficient CHO and human cancer cells. Clonogenic assays, alkaline COMET assays, γH2AX immunocytochemistry, FACS for cell cycle as well as FITC-annexin V flow cytometric analysis were performed.
Results
ATR inhibition is synthetically lethal in XRCC1 deficient cells as evidenced by increased cytotoxicity, accumulation of double strand DNA breaks, G2/M cell cycle arrest and increased apoptosis. Compared to cisplatin alone, combination of cisplatin and ATR inhibitor results in enhanced cytotoxicity in XRCC1 deficient cells compared to XRCC1 proficient cells.
Conclusions
Our data provides evidence that ATR inhibition is suitable for synthetic lethality application and cisplatin chemopotentiation in XRCC1 deficient ovarian cancer cells |
| first_indexed | 2025-11-14T18:18:25Z |
| format | Article |
| id | nottingham-2510 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T18:18:25Z |
| publishDate | 2013 |
| publisher | Public Library of Science |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-25102020-05-04T16:35:45Z https://eprints.nottingham.ac.uk/2510/ Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells Sultana, Rebeka Abdel-Fatah, Tarek Perry, Christina Moseley, Paul Albarakti, Nada Mohan, Vivek Seedhouse, Claire Chan, Stephan Madhusudan, Srinivasan Introduction Ataxia telangiectasia mutated and Rad3 Related (ATR) protein kinase is a key sensor of single-stranded DNA associated with stalled replication forks and repair intermediates generated during DNA repair. XRCC1 is a critical enzyme in single strand break repair and base excision repair. XRCC1-LIG3 complex is also an important contributor to the ligation step of the nucleotide excision repair response. Methods In the current study, we investigated synthetic lethality in XRCC1 deficient and XRCC1 proficient Chinese Hamster ovary (CHO) and human ovarian cancer cells using ATR inhibitors (NU6027). In addition, we also investigated the ability of ATR inhibitors to potentiate cisplatin cytotoxicity in XRCC1 deficient and XRCC1 proficient CHO and human cancer cells. Clonogenic assays, alkaline COMET assays, γH2AX immunocytochemistry, FACS for cell cycle as well as FITC-annexin V flow cytometric analysis were performed. Results ATR inhibition is synthetically lethal in XRCC1 deficient cells as evidenced by increased cytotoxicity, accumulation of double strand DNA breaks, G2/M cell cycle arrest and increased apoptosis. Compared to cisplatin alone, combination of cisplatin and ATR inhibitor results in enhanced cytotoxicity in XRCC1 deficient cells compared to XRCC1 proficient cells. Conclusions Our data provides evidence that ATR inhibition is suitable for synthetic lethality application and cisplatin chemopotentiation in XRCC1 deficient ovarian cancer cells Public Library of Science 2013-02-25 Article PeerReviewed Sultana, Rebeka, Abdel-Fatah, Tarek, Perry, Christina, Moseley, Paul, Albarakti, Nada, Mohan, Vivek, Seedhouse, Claire, Chan, Stephan and Madhusudan, Srinivasan (2013) Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells. PLoS ONE, 8 (2). e57098/1-e57098/9. ISSN 1932-6203 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0057098 doi:10.1371/journal.pone.0057098 doi:10.1371/journal.pone.0057098 |
| spellingShingle | Sultana, Rebeka Abdel-Fatah, Tarek Perry, Christina Moseley, Paul Albarakti, Nada Mohan, Vivek Seedhouse, Claire Chan, Stephan Madhusudan, Srinivasan Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells |
| title | Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells |
| title_full | Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells |
| title_fullStr | Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells |
| title_full_unstemmed | Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells |
| title_short | Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells |
| title_sort | ataxia telangiectasia mutated and rad3 related (atr) protein kinase inhibition is synthetically lethal in xrcc1 deficient ovarian cancer cells |
| url | https://eprints.nottingham.ac.uk/2510/ https://eprints.nottingham.ac.uk/2510/ https://eprints.nottingham.ac.uk/2510/ |