CDK9-55 guides the anaphase-promoting complex/cyclosome (APC/C) in choosing the DNA repair pathway choice.
Luigi AlfanoCarmelina Antonella IannuzziDaniela BaroneIris Maria ForteMaria Carmen RagostaMaria CuomoGiulio MazzarottiMilena Dell'AquilaAngela AltieriAntonella CaporasoCristin RomaLaura MarraSilvia BoffoPaola IndovinaMichelino De LaurentiisAntonio GiordanoPublished in: Oncogene (2024)
DNA double-strand breaks (DSBs) contribute to genome instability, a key feature of cancer. DSBs are mainly repaired by homologous recombination (HR) and non-homologous end-joining (NHEJ). We investigated the role of an isoform of the multifunctional cyclin-dependent kinase 9, CDK9-55, in DNA repair, by generating CDK9-55-knockout HeLa clones (through CRISPR-Cas9), which showed potential HR dysfunction. A phosphoproteomic screening in these clones treated with camptothecin revealed that CDC23 (cell division cycle 23), a component of the E3-ubiquitin ligase APC/C (anaphase-promoting complex/cyclosome), is a new substrate of CDK9-55, with S588 being its putative phosphorylation site. Mutated non-phosphorylatable CDC23(S588A) affected the repair pathway choice by impairing HR and favouring error-prone NHEJ. This CDK9 role should be considered when designing CDK-inhibitor-based cancer therapies.
Keyphrases
- dna repair
- cell cycle
- dna damage
- cell proliferation
- dna damage response
- crispr cas
- papillary thyroid
- squamous cell
- single cell
- oxidative stress
- cell therapy
- stem cells
- mesenchymal stem cells
- gene expression
- drug delivery
- atomic force microscopy
- single molecule
- cell free
- human health
- climate change
- decision making
- lymph node metastasis
- bone marrow
- wild type