title: RAD51 and BRCA2 Enhance Oncolytic Adenovirus Type 5 Activity in Ovarian Cancer.
abstract: Homologous recombination (HR) function is critically important in high-grade serous ovarian cancer (HGSOC). HGSOC with intact HR has a worse prognosis and is less likely to respond to platinum chemotherapy and PARP inhibitors. Oncolytic adenovirus, a novel therapy for human malignancies, stimulates a potent DNA damage response that influences overall antitumor activity. Here, the importance of HR was investigated by determining the efficacy of adenovirus type 5 (Ad5) vectors in ovarian cancer. Using matched BRCA2-mutant and wild-type HGSOC cells, it was demonstrated that intact HR function promotes viral DNA replication and augments overall efficacy, without influencing viral DNA processing. These data were confirmed in a wider panel of HR competent and defective ovarian cancer lines. Mechanistically, both BRCA2 and RAD51 localize to viral replication centers within the infected cell nucleus and that RAD51 localization occurs independently of BRCA2. In addition, a direct interaction was identified between RAD51 and adenovirus E2 DNA binding protein. Finally, using functional assays of HR competence, despite inducing degradation of MRE11, Ad5 infection does not alter cellular ability to repair DNA double-strand break damage via HR. These data reveal that Ad5 redistributes critical HR components to viral replication centers and enhances cytotoxicity.
  
  
  CONCLUSIONS
  Oncolytic adenoviral therapy may be most clinically relevant in tumors with intact HR function.
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Tookman
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Ashley K
authors.initials: AK
authors.lastname: Browne
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Claire M
authors.initials: CM
authors.lastname: Connell
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Gemma
authors.initials: G
authors.lastname: Bridge
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Carin K
authors.initials: CK
authors.lastname: Ingemarsdotter
authors.affiliation: Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Dowson
authors.affiliation: Advanced Scientific Research Leaders Development Unit, Gunma University, Maebashi, Gunma, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shibata
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Michelle
authors.initials: M
authors.lastname: Lockley
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Martin
authors.affiliation: Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom. Iain.mcneish@glasgow.ac.uk.
authors.forename: Iain A
authors.initials: IA
authors.lastname: McNeish
mesh_terms: D000256:Adenoviridae / Q000235:genetics / Q000502:physiology*; D017502:Adenovirus E2 Proteins / Q000378:metabolism; D024682:BRCA2 Protein / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D005260:Female; D005822:Genetic Vectors / Q000494:pharmacology; D059765:Homologous Recombination; D006801:Humans; D050130:Oncolytic Virotherapy; D010051:Ovarian Neoplasms / Q000378:metabolism*; D051135:Rad51 Recombinase / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D017502:Adenovirus E2 Proteins; D024682:BRCA2 Protein; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D002945:Cisplatin