MRNIP/C5orf45 Interacts with the MRN Complex and Contributes to the DNA Damage Response
Christopher J. Staples,
Giancarlo Barone,
Katie N. Myers,
Anil Ganesh,
Ian Gibbs-Seymour,
Abhijit A. Patil,
Ryan D. Beveridge,
Caroline Daye,
Richard Beniston,
Sarah Maslen,
Ivan Ahel,
J. Mark Skehel,
Spencer J. Collis
Affiliations
Christopher J. Staples
Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, Academic Unit of Molecular Oncology, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK
Giancarlo Barone
Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, Academic Unit of Molecular Oncology, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK
Katie N. Myers
Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, Academic Unit of Molecular Oncology, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK
Anil Ganesh
Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, Academic Unit of Molecular Oncology, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK
Ian Gibbs-Seymour
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK
Abhijit A. Patil
Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, Academic Unit of Molecular Oncology, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK
Ryan D. Beveridge
Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, Academic Unit of Molecular Oncology, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK
Caroline Daye
Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, Academic Unit of Molecular Oncology, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK
Richard Beniston
Biological Mass Spectrometry Facility biOMICS, University of Sheffield, Brook Hill Road, Sheffield S3 7HF, UK
Sarah Maslen
Division of Cell Biology, Mass Spectrometry Group, The MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
Ivan Ahel
Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK
J. Mark Skehel
Division of Cell Biology, Mass Spectrometry Group, The MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK
Spencer J. Collis
Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, Academic Unit of Molecular Oncology, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK
Through an RNAi-based screen for previously uncharacterized regulators of genome stability, we have identified the human protein C5orf45 as an important factor in preventing the accumulation of DNA damage in human cells. Here, we functionally characterize C5orf45 as a binding partner of the MRE11-RAD50-NBS1 (MRN) damage-sensing complex. Hence, we rename C5orf45 as MRNIP for MRN-interacting protein (MRNIP). We find that MRNIP is rapidly recruited to sites of DNA damage. Cells depleted of MRNIP display impaired chromatin loading of the MRN complex, resulting in reduced DNA end resection and defective ATM-mediated DNA damage signaling, a reduced ability to repair DNA breaks, and radiation sensitivity. Finally, we show that MRNIP phosphorylation on serine 115 leads to its nuclear localization, and this modification is required for MRNIP’s role in promoting genome stability. Collectively, these data reveal that MRNIP is an important component of the human DNA damage response.
