Cullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnover to fine-tune DNA-end resection

Lorenza P Ferretti, Sarah-Felicitas Himmels, Anika Trenner, Christina Walker, Christine von Aesch, Aline Eggenschwiler, Olga Murina, Radoslav I Enchev, Matthias Peter, Raimundo Freire, Antonio Porro, Alessandro A Sartori

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Human CtIP is a decisive factor in DNA double-strand break repair pathway choice by enabling DNA-end resection, the first step that differentiates homologous recombination (HR) from non-homologous end-joining (NHEJ). To coordinate appropriate and timely execution of DNA-end resection, CtIP function is tightly controlled by multiple protein-protein interactions and post-translational modifications. Here, we identify the Cullin3 E3 ligase substrate adaptor Kelch-like protein 15 (KLHL15) as a new interaction partner of CtIP and show that KLHL15 promotes CtIP protein turnover via the ubiquitin-proteasome pathway. A tripeptide motif (FRY) conserved across vertebrate CtIP proteins is essential for KLHL15-binding; its mutation blocks KLHL15-dependent CtIP ubiquitination and degradation. Consequently, DNA-end resection is strongly attenuated in cells overexpressing KLHL15 but amplified in cells either expressing a CtIP-FRY mutant or lacking KLHL15, thus impacting the balance between HR and NHEJ. Collectively, our findings underline the key importance and high complexity of CtIP modulation for genome integrity.

Original languageEnglish
Pages (from-to)12628
JournalNature Communications
Publication statusPublished - 26 Aug 2016

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  • Journal Article


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