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 and Alessandro A. Sartori ()
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Lorenza P. Ferretti: University of Zurich, Institute of Molecular Cancer Research
Sarah-Felicitas Himmels: University of Zurich, Institute of Molecular Cancer Research
Anika Trenner: University of Zurich, Institute of Molecular Cancer Research
Christina Walker: University of Zurich, Institute of Molecular Cancer Research
Christine von Aesch: University of Zurich, Institute of Molecular Cancer Research
Aline Eggenschwiler: University of Zurich, Institute of Molecular Cancer Research
Olga Murina: University of Zurich, Institute of Molecular Cancer Research
Radoslav I. Enchev: ETH Zurich, Institute of Biochemistry
Matthias Peter: ETH Zurich, Institute of Biochemistry
Raimundo Freire: Unidad de Investigación, Hospital Universitario de Canarias, Instituto de Tecnologías Biomédicas
Antonio Porro: University of Zurich, Institute of Molecular Cancer Research
Alessandro A. Sartori: University of Zurich, Institute of Molecular Cancer Research

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms12628

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