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

Autor: Ma J; Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China., Ren D; Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China., Wang Z; Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China., Li W; Department of Urology, The Second Xiangya Hospital, Central South University, Changsha 410011, China., Li L; Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China., Liu T; Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China., Ye Q; Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China., Lei Y; Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China., Jian Y; Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China., Ma B; Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China., Fan Y; Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China., Liu J; Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China., Gao Y; Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China., Jin X; Department of Urology, The Second Xiangya Hospital, Central South University, Changsha 410011, China., Huang H; Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA.; Institute of Urologic Science and Technology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 311100, China.; Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 311100, China., Li L; Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
Jazyk: angličtina
Zdroj: Science advances [Sci Adv] 2024 May 24; Vol. 10 (21), pp. eadk8908. Date of Electronic Publication: 2024 May 23.
DOI: 10.1126/sciadv.adk8908
Abstrakt: 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.
Databáze: MEDLINE
Externí odkaz: