期刊
BIOCHEMICAL PHARMACOLOGY
卷 193, 期 -, 页码 -出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2021.114767
关键词
DNA Holliday junction; Small molecule stabilizer; Homologous recombination repair; DNA damage response; Telomeric DNA damage; Anti-osteosarcoma
资金
- Natural Science Foundation of Shandong Province [ZR2020QB162]
- National Natural Science Foun-dation of China [82073888]
- National Natural Science Foundation of China [82104006]
- Science and Technology Support Program for Youth Innovation in Universities of Shandong [2019KJM009]
- Top Talents Program for One Case Discussion of Shandong Province
- Talent Induction Program for Youth Innovation Teams in Colleges and Uni-versities of Shandong Province
- Graduate Innovation Foundation of Yantai University
VE-822 was identified as an effective DNA Holliday junction stabilizer, promoting homologous recombination repair, DNA damage response, and sensitizing osteosarcoma cells to doxorubicin.
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.
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