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

• DOI: 10.1038/ncomms12628
• Publication Date: 2016-08-26T09:27:55Z
• Authors: Lorenza P. Ferretti; Sarah-Felicitas H...; Anika Trenner; Christina Walker; Christine von Aesch; Aline Eggenschwiler; Olga Murina; Radoslav I. Enchev; Matthias Peter; Raimundo Freire; Antonio Porro; Alessandro A. Sar...
• Keywords: DDB1; Non-homologous end joining

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 function tightly controlled multiple protein–protein interactions post-translational modifications. Here, we identify Cullin3 E3 ligase substrate adaptor Kelch-like protein 15 (KLHL15) as new interaction partner show KLHL15 promotes turnover via ubiquitin-proteasome pathway. A tripeptide motif (FRY) conserved across vertebrate proteins essential for KLHL15-binding; its mutation blocks KLHL15-dependent ubiquitination degradation. Consequently, resection strongly attenuated cells overexpressing but amplified either expressing CtIP-FRY mutant or lacking KLHL15, thus impacting balance between HR NHEJ. Collectively, our findings underline key importance high complexity modulation genome integrity.