CK2-dependent degradation of CBX3 dictates replication fork stalling and PARP inhibitor sensitivity

作者：Jian Ma, Dianyun Ren, Zixi Wang, Wei Li, Lei Li, Lei Li, Tianjie Liu, Qi Ye, Yuzeshi Lei, Yanlin Jian, Bohan Ma, Yizeng Fan, Jing Liu, Yang Gao, Xin Jin, Haojie Huang, Lei Li, Lei Li · 发表于：Science Advances · 年份：2024 · DOI：10.1126/sciadv.adk8908 · 被引用次数：6 · 研究领域：DNA Repair Mechanisms、PARP inhibition in cancer therapy、Genomics and Chromatin Dynamics

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.