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

Area of Science:

• Molecular Biology
• Cancer Research
• DNA Repair Mechanisms

Background:

• Loss of Histone Deacetylase 5 (HDAC5) is linked to poor survival in pancreatic ductal adenocarcinoma (PDAC).
• The precise role of HDAC5 in regulating DNA double-strand break (DSB) repair pathway choice is not fully understood.

Purpose of the Study:

• To elucidate the molecular mechanisms by which HDAC5 influences DNA end resection and homologous recombination (HR) in PDAC.
• To investigate the signaling axis regulating HDAC5 activity and its impact on DNA repair.

Main Methods:

• Utilized PDAC cell lines, genetically engineered mouse models, and patient-derived organoids.
• Performed biochemical assays, analyzed protein interactions, post-translational modifications, and cellular responses to DNA damage and PARP inhibition.

Main Results:

• Identified HDAC5 as a key regulator of DNA end resection and HR via Ku70 deacetylation.
• Discovered that Casein Kinase 2 (CK2) phosphorylates HDAC5, promoting its nuclear entry and subsequent Ku70 deacetylation at lysine 287.
• Demonstrated that HDAC5 deficiency or CK2 inhibition impairs DNA end resection and homologous recombination, increasing sensitivity to PARP inhibitors.

Conclusions:

• Uncovered a novel CK2-HDAC5-Ku70 signaling axis controlling DNA repair pathway choice by regulating DNA end resection.
• This axis provides a mechanistic basis for enhancing PARP inhibitor efficacy in PDAC, even in tumors lacking classical homologous recombination deficiency.