TY - JOUR
T1 - Nimbolide targets RNF114 to induce the trapping of PARP1 and synthetic lethality in BRCA-mutated cancer
AU - Li, Peng
AU - Zhen, Yuanli
AU - Kim, Chiho
AU - Liu, Zhengshuai
AU - Hao, Jianwei
AU - Deng, Heping
AU - Deng, Hejun
AU - Zhou, Min
AU - Wang, Xu Dong
AU - Qin, Tian
AU - Yu, Yonghao
N1 - Publisher Copyright:
© 2023 The Authors.
PY - 2023/10
Y1 - 2023/10
N2 - Recent studies have pointed to PARP1 trapping as a key determinant of the anticancer effects of PARP1 inhibitors (PARPi). We identified RNF114, as a PARylation-dependent, E3 ubiquitin ligase involved in DNA damage response. Upon sensing genotoxicity, RNF114was recruited, in a PAR-dependent manner, to DNA lesions, where it targeted PARP1 for degradation. The blockade of this pathway interfered with the removal of PARP1 from DNA lesions, leading to profound PARP1 trapping. We showed that a natural product, nimbolide, inhibited the E3 ligase activity of RNF114 and thus caused PARP1 trapping. However, unlike conventional PARPi, nimbolide treatment induced the trapping of both PARP1 and PARylation-dependent DNA repair factors. Nimbolide showed synthetic lethality with BRCA mutations, and it overcame intrinsic and acquired resistance to PARPi, both in vitro and in vivo. These results point to the exciting possibility of targeting the RNF114-PARP1 pathway for the treatment of homologous recombination-deficient cancers.
AB - Recent studies have pointed to PARP1 trapping as a key determinant of the anticancer effects of PARP1 inhibitors (PARPi). We identified RNF114, as a PARylation-dependent, E3 ubiquitin ligase involved in DNA damage response. Upon sensing genotoxicity, RNF114was recruited, in a PAR-dependent manner, to DNA lesions, where it targeted PARP1 for degradation. The blockade of this pathway interfered with the removal of PARP1 from DNA lesions, leading to profound PARP1 trapping. We showed that a natural product, nimbolide, inhibited the E3 ligase activity of RNF114 and thus caused PARP1 trapping. However, unlike conventional PARPi, nimbolide treatment induced the trapping of both PARP1 and PARylation-dependent DNA repair factors. Nimbolide showed synthetic lethality with BRCA mutations, and it overcame intrinsic and acquired resistance to PARPi, both in vitro and in vivo. These results point to the exciting possibility of targeting the RNF114-PARP1 pathway for the treatment of homologous recombination-deficient cancers.
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U2 - 10.1126/sciadv.adg7752
DO - 10.1126/sciadv.adg7752
M3 - Article
C2 - 37878693
AN - SCOPUS:85175219015
SN - 2375-2548
VL - 9
JO - Science Advances
JF - Science Advances
IS - 43
M1 - eadg7752
ER -