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Cullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnover to fine-tune DNA-end resection
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Cullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnover to fine-tune DNA-end resection
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Cullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnover to fine-tune DNA-end resection
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Journal Article
Cullin3-KLHL15 ubiquitin ligase mediates CtIP protein turnover to fine-tune DNA-end resection
2016
Overview
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.
CtIP has a key role in DNA double-strand break repair as its role in resecting DNA at the break commits a cell to homologous recombination. Here the authors show that KLHL15 interacts with CtIP and regulates repair by controlling protein turnover.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
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/ 13/44
/ 13/89
/ 14/35
/ 14/63
/ 38/23
/ 38/70
/ 82/16
/ 82/29
/ 82/58
/ 82/80
/ 82/83
/ Carrier Proteins - metabolism
/ Cullin Proteins - metabolism
/ DNA
/ Enzymes
/ Genomes
/ Homologous Recombination - genetics
/ Humanities and Social Sciences
/ Humans
/ Microfilament Proteins - metabolism
/ Mutation
/ Nuclear Proteins - metabolism
/ Protein Interaction Domains and Motifs - genetics
/ Proteins
/ Science
/ Yeast
