Depletion of DNA damage binding protein 2 sensitizes triple‐negative breast cancer cells to poly ADP‐ribose polymerase inhibition by destabilizing Rad51. Issue 11 (6th October 2019)

• Record Type: Journal Article
• Authors: Zhao, Lin; Si, Cheng‐Shuai; Yu, Yue; Lu, Jian‐Wei; Zhuang, Yan
• Is Part Of: Cancer science. Volume 110:Issue 11(2019)
• Page Start: 3543
• Page End: 3552
• Publication Date: 2019-10-06
• Subjects: DDB2 -- homologous recombination -- PARPi sensitivity -- Rad51 -- triple‐negative breast cancer; Cancer -- Periodicals; Neoplasms -- Periodicals; Research -- Periodicals; Electronic journals; 616.994005
• DOI: 10.1111/cas.14201
• Languages: English
• ISSNs: 1347-9032

Abstract

Abstract: Poly ADP‐ribose polymerase inhibitors (PARPi) have shown promising therapeutic efficacy in triple‐negative breast cancer (TNBC) patients. However, resistance ultimately develops, preventing a curative effect from being attained. Extensive investigations have indicated the diversity in the mechanisms underlying the PARPi sensitivity of breast cancer. In this study, we found that DNA damage binding protein 2 (DDB2), a DNA damage‐recognition factor, could protect TNBC cells from PARPi by regulating DNA double‐strand break repair through the homologous recombination pathway, whereas the depletion of DDB2 sensitizes TNBC cells to PARPi. Furthermore, we found that DDB2 was able to stabilize Rad51 by physical association and disrupting its ubiquitination pathway‐induced proteasomal degradation. These findings highlight an essential role of DDB2 in modulating homologous recombination pathway activity and suggest a promising therapeutic target for TNBC. Abstract : We found that DNA damage binding protein 2 (DDB2), a DNA damage‐recognition factor, could protect triple‐negative breast cancer (TNBC) cells from poly ADP‐ribose polymerase inhibitors by regulating the homologous recombination pathway of DNA double‐strand break repair, whereas the depletion of DDB2 sensitizes TNBC cells to poly ADP‐ribose polymerase inhibitors. Furthermore, we found that DDB2 was able to stabilize Rad51 by disrupting its ubiquitination pathway‐induced proteasomal degradation. These findings highlight an essential role of DDB2 in modulating homologous recombination pathway activity and suggest a potential therapeutic target for TNBC.