CK2-dependent degradation of CBX3 dictates replication fork stalling and PARP inhibitor sensitivity
CK2-dependent degradation of CBX3 dictates replication fork stalling and PARP inhibitor sensitivity
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DOI：
10.1126/sciadv.adk8908
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发表时间：
2024-05-23
期刊：
影响因子：
13.6
通讯作者：
Li，Lei
中科院分区：
文献类型：
--
作者：
Ma，Jian;Ren，Dianyun;Li，Lei
DNA复制是一个脆弱的细胞过程，其失调导致基因组不稳定。在这里，我们证明了染色体盒蛋白同源物3（CBX 3）结合复制蛋白A 32 kDa亚基（RPA 2），并调节RPA 2保留在停滞的复制叉。CBX 3被RPA 2募集到停滞的复制叉，并抑制环指和WD重复结构域3（RFWD 3）促进的复制重启。通过酪蛋白激酶2（CK 2）激酶在丝氨酸-95处对CBX 3进行磷酸化增强了钙粘蛋白1（CDH 1）介导的CBX 3降解和停滞复制叉处的RPA 2动力学，这允许复制叉重新启动。由于基因扩增或CK 2抑制剂治疗引起的CBX 3表达增加使前列腺癌细胞对聚（ADP-核糖）聚合酶（PARP）抑制剂敏感，同时诱导复制应激和DNA损伤。我们的工作揭示了CBX 3作为RPA 2功能和DNA复制的关键调节因子，这表明CBX 3可以作为使用PARP抑制剂进行癌症靶向治疗的指示剂。
DNA replication is a vulnerable cellular process, and its deregulation leads to genomic instability. Here, we demonstrate that chromobox protein homolog 3 (CBX3) binds replication protein A 32-kDa subunit (RPA2) and regulates RPA2 retention at stalled replication forks. CBX3 is recruited to stalled replication forks by RPA2 and inhibits ring finger and WD repeat domain 3 (RFWD3)–facilitated replication restart. Phosphorylation of CBX3 at serine-95 by casein kinase 2 (CK2) kinase augments cadherin 1 (CDH1)–mediated CBX3 degradation and RPA2 dynamics at stalled replication forks, which permits replication fork restart. Increased expression of CBX3 due to gene amplification or CK2 inhibitor treatment sensitizes prostate cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors while inducing replication stress and DNA damage. Our work reveals CBX3 as a key regulator of RPA2 function and DNA replication, suggesting that CBX3 could serve as an indicator for targeted therapy of cancer using PARP inhibitors.