@article{b1dbc9a7497a48bea040bd09ecf2a89d,
title = "MRI Is a DNA Damage Response Adaptor during Classical Non-homologous End Joining",
abstract = "The modulator of retrovirus infection (MRI or CYREN) is a 30-kDa protein with a conserved N-terminal Ku-binding motif (KBM) and a C-terminal XLF-like motif (XLM). We show that MRI is intrinsically disordered and interacts with many DNA damage response (DDR) proteins, including the kinases ataxia telangiectasia mutated (ATM) and DNA-PKcs and the classical non-homologous end joining (cNHEJ) factors Ku70, Ku80, XRCC4, XLF, PAXX, and XRCC4. MRI forms large multimeric complexes that depend on its N and C termini and localizes to DNA double-strand breaks (DSBs), where it promotes the retention of DDR factors. Mice deficient in MRI and XLF exhibit embryonic lethality at a stage similar to those deficient in the core cNHEJ factors XRCC4 or DNA ligase IV. Moreover, MRI is required for cNHEJ-mediated DSB repair in XLF-deficient lymphocytes. We propose that MRI is an adaptor that, through multivalent interactions, increases the avidity of DDR factors to DSB-associated chromatin to promote cNHEJ. Hung et al. demonstrate that MRI is a disordered protein that functions in DSB repair and is essential for cNHEJ in the absence of XLF. MRI interacts with cNHEJ and DDR signaling factors at its termini and promotes the avidity of these proteins for chromatin in response to DNA damage.",
keywords = "CYREN, DNA double-strand break repair, MRI, V(D)J recombination, adaptor protein, non-homologous end joining",
author = "Hung, {Putzer J.} and Britney Johnson and Chen, {Bo Ruei} and Byrum, {Andrea K.} and Bredemeyer, {Andrea L.} and Yewdell, {William T.} and Johnson, {Tanya E.} and Lee, {Brian J.} and Shruthi Deivasigamani and Issa Hindi and Parmeshwar Amatya and Gross, {Michael L.} and Paull, {Tanya T.} and Pisapia, {David J.} and Jayanta Chaudhuri and Petrini, {John J.H.} and Nima Mosammaparast and Amarasinghe, {Gaya K.} and Shan Zha and Tyler, {Jessica K.} and Sleckman, {Barry P.}",
note = "Funding Information: This work was supported by NIH grants AI047829 (B.P.S.), AI074953 (B.P.S.), AI120943 (G.K.A.), CA193318 (N.M.), GM59413 (J.J.H.P.), and CA184187 (S.Z.) as well as the Alvin Siteman Cancer Research Fund (N.M.). The mass spectrometry research was supported in part by NIH grant P41GM103422 (M.L.G.). We thank Drs. H. Rohrs and D. Leung for discussion and guidance with the characterization of MRI by biophysical methods. We thank S.Z. Duan for assistance with immunohistochemistry. We thank Dr. Kathy Sheehan and the Washington University School of Medicine, Department of Pathology and Immunology Hybridoma Center for monoclonal antibody development. Funding Information: This work was supported by NIH grants AI047829 (B.P.S.), AI074953 (B.P.S.), AI120943 (G.K.A.), CA193318 (N.M.), GM59413 (J.J.H.P.), and CA184187 (S.Z.) as well as the Alvin Siteman Cancer Research Fund (N.M.). The mass spectrometry research was supported in part by NIH grant P41GM103422 (M.L.G.). We thank Drs. H. Rohrs and D. Leung for discussion and guidance with the characterization of MRI by biophysical methods. We thank S.Z. Duan for assistance with immunohistochemistry. We thank Dr. Kathy Sheehan and the Washington University School of Medicine, Department of Pathology and Immunology Hybridoma Center for monoclonal antibody development. Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2018",
month = jul,
day = "19",
doi = "10.1016/j.molcel.2018.06.018",
language = "English",
volume = "71",
pages = "332--342.e8",
journal = "Molecular Cell",
issn = "1097-2765",
number = "2",
}