# CK2-mediated HDAC5 shuttling regulates DNA end resection through Ku70 deacetylation

## TL;DR

This study reveals how HDAC5, regulated by CK2, controls DNA repair by deacetylating Ku70, influencing cancer cell response to PARP inhibitors.

## Contribution

Discovery of a novel CK2-HDAC5-Ku70 signaling axis regulating DNA end resection and homologous recombination in DNA repair.

## Key findings

- HDAC5 deacetylates Ku70 at lysine 287, enabling DNA end resection and homologous recombination repair.
- HDAC5 loss or CK2 inhibition impairs DNA repair and increases PARP inhibitor sensitivity in PDAC cells.
- Pharmacological CK2 inhibition sensitizes HDAC5-proficient tumors to PARP inhibition.

## Abstract

Rationale: Loss of histone deacetylase 5 (HDAC5) is frequently observed in multiple malignancies, including pancreatic ductal adenocarcinoma (PDAC), and is associated with poor patient survival. Although HDAC5 has been implicated in DNA damage repair, the molecular mechanisms by which it regulates DNA double-strand break (DSB) repair pathway choice remain unclear.

Methods: Using PDAC cell lines, genetically engineered mouse models, patient-derived organoids, and biochemical assays, we investigated the role of HDAC5 in DNA end resection and homologous recombination (HR). Protein interactions, post-translational modifications, DNA repair pathway activity, and cellular responses to DNA damage and PARP inhibition were systematically analyzed.

Results: We identify HDAC5 as a critical regulator of DNA end resection and HR through deacetylation of Ku70. DNA damage induces casein kinase 2 (CK2)-mediated phosphorylation of HDAC5, promoting its nuclear translocation. Nuclear HDAC5 directly deacetylates Ku70 at lysine 287, facilitating Ku70 dissociation from DSB sites, thereby enabling DNA end resection and HR repair. In contrast, HDAC5 loss or CK2 inhibition results in Ku70 K287 hyperacetylation, prolonged retention of the Ku heterodimer at DSBs, impaired DNA end resection, and suppression of HR. Consequently, HDAC5-deficient PDAC cells exhibit increased sensitivity to PARP inhibitors, while pharmacological CK2 inhibition sensitizes HDAC5-proficient tumors to PARP inhibition.

Conclusions: These findings uncover a previously unrecognized CK2-HDAC5-Ku70 signaling axis that governs DNA repair pathway choice by regulating DNA end resection. Targeting this axis provides a mechanistic rationale for enhancing PARP inhibitor sensitivity in PDAC, including tumors without classical homologous recombination deficiency.