The Intermediate Filament Synemin Regulates Non-Homologous End Joining in an ATM-Dependent Manner.

Sara Sofia Deville,Nils Cordes,Kerstin Borgmann,Ellen Dickreuter,Anne Vehlow,Sarah Förster

doi:10.3390/cancers12071717

Abstract

The treatment resistance of cancer cells is a multifaceted process in which DNA repair emerged as a potential therapeutic target. DNA repair is predominantly conducted by nuclear events; yet, how extra-nuclear cues impact the DNA damage response is largely unknown. Here, using a high-throughput RNAi-based screen in three-dimensionally-grown cell cultures of head and neck squamous cell carcinoma (HNSCC), we identified novel focal adhesion proteins controlling DNA repair, including the intermediate filament protein, synemin. We demonstrate that synemin critically regulates the DNA damage response by non-homologous end joining repair. Mechanistically, synemin forms a protein complex with DNA-PKcs through its C-terminal tail domain for determining DNA repair processes upstream of this enzyme in an ATM-dependent manner. Our study discovers a critical function of the intermediate filament protein, synemin in the DNA damage response, fundamentally supporting the concept of cytoarchitectural elements as co-regulators of nuclear events.

Highlights

DNA double strand breaks (DSB) are the most lethal damages generated by genotoxic agents, such as ionizing radiation (IR) and chemotherapeutics [1], accounting for the therapeutic benefit of current cancer treatment modalities
In an Ataxia telangiectasia mutated (ATM)-dependent manner, synemin serves as a scaffold for DNA-PKcs and co-determines DSB repair upon genotoxic injury
Our data pinpoint the multifaceted roles of intermediate filaments and the regulatory complexity of DNA repair processes

Summary

Introduction

DNA double strand breaks (DSB) are the most lethal damages generated by genotoxic agents, such as ionizing radiation (IR) and chemotherapeutics [1], accounting for the therapeutic benefit of current cancer treatment modalities. These complex DNA lesions are repaired by two major cellular mechanisms: Non-homologous end joining (NHEJ) and homologous recombination (HR) [2,3]. While HR is mostly regarded as an error-free repair process restricted to the S/G2 phase, NHEJ is error-prone and active throughout the mammalian cell cycle [5]. The nucleases Artemis, Aprataxin or APLF are recruited to complete the end processing, together with ligases IV, XRCC4, XLF and PAXX, as well as numerous chromatin and nuclear matrix remodeling enzymes to allow for the maintenance of genomic stability [5]

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