多聚[腺苷二磷酸核糖]聚合酶（PARP）抑制剂能够选择性地杀灭同源重组（HR）修复缺陷的癌细胞，被广泛用于治疗携带BRCA1/2突变的癌症患者。然而，它们在野生型（WT）BRCA1/2肿瘤中的疗效有限。因此，通过联合治疗识别新的可药物靶向的HR修复调控因子，并提高PARP抑制剂在BRCA1/2-WT肿瘤中的治疗效果至关重要。在这里，我们展示了核苷酸还原酶（RNR）亚基p53R2缺乏会损害HR修复并使BRCA1/2-WT癌细胞对PARP抑制剂敏感。我们进一步证明p53R2的丧失导致HR修复因子CtIP的减少，这是由于dNTP的短缺引起CtIP泛素化。此外，我们发现酪氨酸激酶II（CK2）磷酸化p53R2的ser20位点，进而激活RNR产生dNTPs。因此，通过药物抑制CK2介导的p53R2的磷酸化，可以削弱其在BRCA1/2-WT癌细胞中的HR修复能力，使这些细胞在体外和体内对PARP抑制剂敏感。因此，我们的研究揭示了一种新的策略，通过合成致死性联合作用抑制HR修复活性，并使BRCA1/2阳性癌症对PARP抑制剂敏感。©2023 作者以排他性许可授权给Springer Nature Limited。

Poly[ADP-ribose] polymerase (PARP) inhibitors, which selectively kills homologous recombination (HR) repair-deficient cancer cells, are widely employed to treat cancer patients harboring BRCA1/2 mutations. However, they display limited efficacy in tumors with wild-type (WT) BRCA1/2. Thus, it is crucial to identify new druggable HR repair regulators and improve the therapeutic efficacy of PARP inhibitors via combination therapies in BRCA1/2-WT tumors. Here, we show that the depletion of ribonucleotide reductase (RNR) subunit p53R2 impairs HR repair and sensitizes BRCA1/2-WT cancer cells to PARP inhibition. We further demonstrate that the loss of p53R2 leads to a decrease of HR repair factor CtIP, as a result of dNTPs shortage-induced ubiquitination of CtIP. Moreover, we identify that casein kinase II (CK2) phosphorylates p53R2 at its ser20, which subsequently activates RNR for dNTPs production. Therefore, pharmacologic inhibition of the CK2-mediated phosphorylation of p53R2 compromises its HR repair capacity in BRCA1/2-WT cancer cells, which renders these cells susceptible to PARP inhibition in vitro and in vivo. Therefore, our study reveals a novel strategy to inhibit HR repair activity and convert BRCA1/2-proficient cancers to be susceptible to PARP inhibitors via synthetic lethal combination.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.