CK2-dependent degradation of CBX3 dictates replication fork stalling and PARP inhibitor sensitivity.
Sci Adv
; 10(21): eadk8908, 2024 May 24.
Article
in En
| MEDLINE
| ID: mdl-38781342
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Casein Kinase II
/
DNA Replication
/
Replication Protein A
/
Poly(ADP-ribose) Polymerase Inhibitors
Limits:
Humans
Language:
En
Journal:
Sci Adv
Year:
2024
Document type:
Article
Affiliation country:
China
Publication country:
EEUU
/
ESTADOS UNIDOS
/
ESTADOS UNIDOS DA AMERICA
/
EUA
/
UNITED STATES
/
UNITED STATES OF AMERICA
/
US
/
USA