title: MRNIP/C5orf45 Interacts with the MRN Complex and Contributes to the DNA Damage Response.
abstract: 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.
authors: 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.
authors: Christopher J
authors: CJ
authors: Staples
authors: 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.
authors: Giancarlo
authors: G
authors: Barone
authors: 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.
authors: Katie N
authors: KN
authors: Myers
authors: 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.
authors: Anil
authors: A
authors: Ganesh
authors: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
authors: Ian
authors: I
authors: Gibbs-Seymour
authors: 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.
authors: Abhijit A
authors: AA
authors: Patil
authors: 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.
authors: Ryan D
authors: RD
authors: Beveridge
authors: 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.
authors: Caroline
authors: C
authors: Daye
authors: Biological Mass Spectrometry Facility biOMICS, University of Sheffield, Brook Hill Road, Sheffield S3 7HF, UK.
authors: Richard
authors: R
authors: Beniston
authors: Division of Cell Biology, Mass Spectrometry Group, The MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
authors: Sarah
authors: S
authors: Maslen
authors: Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
authors: Ivan
authors: I
authors: Ahel
authors: Division of Cell Biology, Mass Spectrometry Group, The MRC Laboratory of Molecular Biology, Hills Road, Cambridge CB2 0QH, UK.
authors: J Mark
authors: JM
authors: Skehel
authors: 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. Electronic address: s.collis@sheffield.ac.uk.
authors: Spencer J
authors: SJ
authors: Collis
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D064447:Checkpoint Kinase 2 / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair / Q000528:radiation effects; D004706:Endodeoxyribonucleases; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D046912:Multiprotein Complexes / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding / Q000528:radiation effects; D011836:Radiation Tolerance / Q000528:radiation effects; D011839:Radiation, Ionizing; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000528:radiation effects
chemical_list: D002352:Carrier Proteins; D002843:Chromatin; C000624704:MRNIP protein, human; D046912:Multiprotein Complexes; D009687:Nuclear Proteins; D064447:Checkpoint Kinase 2; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D004706:Endodeoxyribonucleases; C410741:RBBP8 protein, human