Poly (ADP-ribose) polymerase inhibitors (PARPi) are used to treat ovarian cancer and triple-negative breast cancer (TNBC) with defective homologous recombination repair pathways. However, de novo and acquired PARPi resistance limits clinical benefits. The MRE11-RAD50-NBS1 (MRN) complex mediates the sensing, processing, and signaling of DNA double-strand breaks (DSBs) and plays important roles in the efficacy of PARPi and radiation treatment, and yet the mechanisms for the regulation and degradation of the MRN complex are not well understood. ZRANB1, also known as Trabid, is a breast cancer-promoting deubiquitinase that preferentially cleaves K29-, K33-, and K63-linked ubiquitin chains, but its role in therapy resistance remains unknown.