Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells.

Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells.

<h4>Introduction</h4>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 bas...

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Autores principales: Rebeka Sultana, Tarek Abdel-Fatah, Christina Perry, Paul Moseley, Nada Albarakti, Vivek Mohan, Claire Seedhouse, Stephen Chan, Srinivasan Madhusudan
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Publicado: Public Library of Science (PLoS) 2013
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spelling oai:doaj.org-article:3418478d6b2648b1a35627002ed8454a2021-11-18T07:56:08ZAtaxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells.1932-620310.1371/journal.pone.0057098https://doaj.org/article/3418478d6b2648b1a35627002ed8454a2013-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/23451157/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203<h4>Introduction</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>Our data provides evidence that ATR inhibition is suitable for synthetic lethality application and cisplatin chemopotentiation in XRCC1 deficient ovarian cancer cells.Rebeka SultanaTarek Abdel-FatahChristina PerryPaul MoseleyNada AlbaraktiVivek MohanClaire SeedhouseStephen ChanSrinivasan MadhusudanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 8, Iss 2, p e57098 (2013)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Rebeka Sultana
Tarek Abdel-Fatah
Christina Perry
Paul Moseley
Nada Albarakti
Vivek Mohan
Claire Seedhouse
Stephen Chan
Srinivasan Madhusudan
Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells.
description <h4>Introduction</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>Our data provides evidence that ATR inhibition is suitable for synthetic lethality application and cisplatin chemopotentiation in XRCC1 deficient ovarian cancer cells.
format article
author Rebeka Sultana
Tarek Abdel-Fatah
Christina Perry
Paul Moseley
Nada Albarakti
Vivek Mohan
Claire Seedhouse
Stephen Chan
Srinivasan Madhusudan
author_facet Rebeka Sultana
Tarek Abdel-Fatah
Christina Perry
Paul Moseley
Nada Albarakti
Vivek Mohan
Claire Seedhouse
Stephen Chan
Srinivasan Madhusudan
author_sort Rebeka Sultana
title 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_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_sort ataxia telangiectasia mutated and rad3 related (atr) protein kinase inhibition is synthetically lethal in xrcc1 deficient ovarian cancer cells.
publisher Public Library of Science (PLoS)
publishDate 2013
url https://doaj.org/article/3418478d6b2648b1a35627002ed8454a
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