title: Ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase inhibition is synthetically lethal in XRCC1 deficient ovarian cancer cells.
abstract: BACKGROUND
  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.
authors: Laboratory of Molecular Oncology, Academic Unit of Oncology, School of Molecular Medical Sciences, University of Nottingham, Nottingham University Hospitals, Nottingham, United Kingdom.
authors: Rebeka
authors: R
authors: Sultana
authors: Tarek
authors: T
authors: Abdel-Fatah
authors: Christina
authors: C
authors: Perry
authors: Paul
authors: P
authors: Moseley
authors: Nada
authors: N
authors: Albarakti
authors: Vivek
authors: V
authors: Mohan
authors: Claire
authors: C
authors: Seedhouse
authors: Stephen
authors: S
authors: Chan
authors: Srinivasan
authors: S
authors: Madhusudan
mesh_terms: D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D016466:CHO Cells; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004268:DNA-Binding Proteins / Q000235:genetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D034741:RNA, Small Interfering; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D034741:RNA, Small Interfering; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases