MassIVE MSV000087856

Partial Public PXD027441

CDK9-55 guides the anaphase-promoting complex/cyclosome (APC/C) in choosing the DNA repair pathway by affecting the UFL1 ubiquitination.

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Description

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-36 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. Moreover, CDC23(S588A) promoted the ubiquitination of UFL1, a recently identified HR player. Overall, CDK9-55 could guide APC/C in choosing the correct DNA repair pathway, possibly by regulating UFL1 stability. This CDK9 role should be considered when designing CDK-inhibitor-based cancer therapies. [doi:10.25345/C5DR7G] [dataset license: CC0 1.0 Universal (CC0 1.0)]

Keywords: Homologous Recombination ; DNA repair pathway choice ; CDK9 ; APC/C ; Phosphoproteomics ; LC-MS/MS

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Principal Investigators:
(in alphabetical order) 		Antonio Giordano, Sbarro Institute for Cancer Research and Molecular Medicine and Center of 16 Biotechnology, College of Science and Technology Temple University, United States
Submitting User: tangh
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