Essential role for DNA-PK-mediated phosphorylation of NR4A nuclear orphan receptors in DNA double-strand break repair

Michal Malewicz, Banafsheh Kadkhodaei, Nigel Kee, Nikolaos Volakakis, Ulf Hellman, Kristina Viktorsson, Chuen Yan Leung, Benjamin Chen, Rolf Lewensohn, Dik C. van Gent, David J. Chen, Thomas Perlmann

Research output: Contribution to journalArticle

56 Scopus citations

Abstract

DNA-dependent protein kinase (DNA-PK) is a central regulator of DNA double-strand break (DSB) repair; however, the identity of relevant DNA-PK substrates has remained elusive. NR4A nuclear orphan receptors function as sequence-specific DNA-binding transcription factors that participate in adaptive and stress-related cell responses. We show here that NR4A proteins interact with the DNA-PK catalytic subunit and, upon exposure to DNA damage, translocate to DSB foci by a mechanism requiring the activity of poly(ADP-ribose) polymerase-1 (PARP-1). At DNA repair foci, NR4A is phosphorylated by DNA-PK and promotes DSB repair. Notably, NR4A transcriptional activity is entirely dispensable in this function, and core components of the DNA repair machinery are not transcriptionally regulated by NR4A. Instead, NR4A functions directly at DNA repair sites by a process that requires phosphorylation by DNA-PK. Furthermore, a severe combined immunodeficiency (SCID)-causing mutation in the human gene encoding the DNA-PK catalytic subunit impairs the interaction and phosphorylation of NR4A at DSBs. Thus, NR4As represent an entirely novel component of DNA damage response and are substrates of DNA-PK in the process of DSB repair.

Original languageEnglish (US)
Pages (from-to)2031-2040
Number of pages10
JournalGenes and Development
Volume25
Issue number19
DOIs
StatePublished - Oct 1 2011

Keywords

  • DNA repair
  • DNA-PK
  • NR4A
  • Nur77
  • Nurr1
  • PARP-1

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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    Malewicz, M., Kadkhodaei, B., Kee, N., Volakakis, N., Hellman, U., Viktorsson, K., Leung, C. Y., Chen, B., Lewensohn, R., van Gent, D. C., Chen, D. J., & Perlmann, T. (2011). Essential role for DNA-PK-mediated phosphorylation of NR4A nuclear orphan receptors in DNA double-strand break repair. Genes and Development, 25(19), 2031-2040. https://doi.org/10.1101/gad.16872411