Nimbolide targets RNF114 to induce the trapping of PARP1 and synthetic lethality in BRCA-mutated cancer

Area of Science:

• Oncology
• Molecular Biology
• DNA Repair Mechanisms

Background:

• Poly (ADP-ribose) polymerase 1 (PARP1) trapping is crucial for the anticancer effects of PARP1 inhibitors (PARPi).
• The DNA damage response pathway involves intricate regulatory mechanisms controlling protein stability and localization at lesion sites.

Purpose of the Study:

• To identify novel regulators of PARP1 stability and localization in response to DNA damage.
• To investigate the therapeutic potential of targeting the RNF114-PARP1 axis in cancer treatment, particularly in homologous recombination-deficient (HRD) cancers.

Main Methods:

• Identification and characterization of RNF114 as a PARylation-dependent E3 ubiquitin ligase.
• Assays to determine RNF114 recruitment to DNA lesions and its role in PARP1 degradation.
• Treatment of cancer cells and in vivo models with nimbolide to assess its effect on RNF114, PARP1 trapping, and therapeutic efficacy.
• Evaluation of nimbolide's efficacy in BRCA-mutated cancer models and in overcoming PARPi resistance.

Main Results:

• RNF114 is recruited to DNA lesions in a PAR-dependent manner and mediates PARP1 degradation.
• Inhibition of RNF114 by nimbolide leads to enhanced PARP1 trapping and trapping of other DNA repair factors.
• Nimbolide demonstrates synthetic lethality with BRCA mutations and overcomes resistance to conventional PARPi in vitro and in vivo.

Conclusions:

• The RNF114-PARP1 pathway is a critical regulator of PARP1 stability and DNA repair.
• Targeting RNF114 with agents like nimbolide represents a novel therapeutic strategy for HRD cancers, including those resistant to PARPi.