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.

External Beam Radiation Therapy and Enadenotucirev: Inhibition of the DDR and Mechanisms of Radiation-Mediated Virus Increase

“…Though the interaction between adenoviral proteins and the NHEJ pathway is relatively well established, we are the first to show inhibition of Rad51 foci formation in adenovirus-infected cells. Co-localisation between viral replication centres and HR has previously been demonstrated with Ad5; however, results were consistent with no effect on HR efficiency in the models used [24].…”

“…Observed in several serotypes, adenoviruses appear to primarily interact with the classical NHEJ pathway through DNA ligase IV degradation [15,23]. The link between adenoviruses and HR is significantly less well established, though data suggests HR proteins seem to be recruited to Ad5 viral replication centres, reportedly improving viral replication and cytotoxicity in cells with functional HR [24].…”

Rare variants in BRCA2 and CHEK2 are associated with the risk of urinary tract cancers

“…BRCA2 (breast cancer early onset 2) is a widely known anti-oncogene and associated with the risk of breast cancer and ovarian cancer 38 . BRCA2 also involves in the maintenance of genome stability through interacting with RAD51 recombinase, specifically in the homologous recombination pathway for DNA repair 39 40 41 . The variant rs11571833 (p.Lys3326X) leads to a stop codon, which results in loss of the final 93 amino acids of the BRCA2 protein.…”

“…The C-terminus of BRCA2 contains a RAD51 binding domain and small protein sequence incorporating p.Lys3326X (amino acids 3265–3330) is capable of binding RAD51. Besides, an important serine involved in BRCA2-mediated repair process is close to this truncating mutation 41 42 43 . Above evidence invites that the SNP rs11571833 is functional in DNA damage repair pathway thus alter the genetic susceptibility of cancers.…”

The MRE11–RAD50–NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair

“…For example, a modified oncolytic adenovirus mutant that lacks an antiapoptotic gene ( E1B19K ) sensitizes pancreatic cells in association with DNA-damage drugs (220), and the proposed mechanism is MRE11 inactivation. For oncolytic adenovirus type 5 being used in ovarian cancer cells (221), virus cytotoxicity is proposed to enable its ability to redistribute MRN (and other HR components). Overall, our evolving knowledge of interactions between viral infection, DNA repair, and the immune response requires defining multiple roles for MRN biochemistry.…”