Homologous recombination repair (HRR) is crucial for genomic stability of cancer cells and is an attractive target in cancer therapy. Holliday junction (HJ) is a four-way DNA intermediate that performs an essential role in homology-directed repair. However, few studies about regulatory mechanisms of HJs have been reported. In this study, to better understand the biological effects of HJs, VE-822 was identified as an effective DNA HJ stabilizer to promote the assembly of HJs both in vitro and in cells. This compound could inhibit the HRR level, activate DNA-PKCS to trigger DNA damage response (DDR) and induce telomeric DNA damage via stabilizing DNA HJs. Furthermore, VE-822 was demonstrated to sensitize the osteosarcoma cells to doxorubicin (Dox) by enhancing DNA damage and cellular apoptosis. This work thus reports one novel HJ stabilizer, and provide a potential anticancer strategy through the modulation of DNA HJs.
Keywords: Anti-osteosarcoma; DNA Holliday junction; DNA damage response; Homologous recombination repair; Small molecule stabilizer; Telomeric DNA damage.
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