MRI Is a DNA Damage Response Adaptor during Classical Non-homologous End Joining

Putzer J. Hung, Britney Johnson, Bo Ruei Chen, Andrea K. Byrum, Andrea L. Bredemeyer, William T. Yewdell, Tanya E. Johnson, Brian J. Lee, Shruthi Deivasigamani, Issa Hindi, Parmeshwar Amatya, Michael L. Gross, Tanya T. Paull, David J. Pisapia, Jayanta Chaudhuri, John J.H. Petrini, Nima Mosammaparast, Gaya K. Amarasinghe, Shan Zha, Jessica K. TylerBarry P. Sleckman

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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.

Original languageEnglish
Pages (from-to)332-342.e8
JournalMolecular cell
Volume71
Issue number2
DOIs
StatePublished - Jul 19 2018

Keywords

  • CYREN
  • DNA double-strand break repair
  • MRI
  • V(D)J recombination
  • adaptor protein
  • non-homologous end joining

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