title: Essential role for DNA-PK-mediated phosphorylation of NR4A nuclear orphan receptors in DNA double-strand break repair.
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.
authors: Ludwig Institute for Cancer Research, Ltd.,Karolinska Institutet, S-171 77 Stockholm, Sweden. michal.malewicz@licr.ki.se
authors: Michal
authors: M
authors: Malewicz
authors: Banafsheh
authors: B
authors: Kadkhodaei
authors: Nigel
authors: N
authors: Kee
authors: Nikolaos
authors: N
authors: Volakakis
authors: Ulf
authors: U
authors: Hellman
authors: Kristina
authors: K
authors: Viktorsson
authors: Chuen Yan
authors: CY
authors: Leung
authors: Benjamin
authors: B
authors: Chen
authors: Rolf
authors: R
authors: Lewensohn
authors: Dik C
authors: DC
authors: van Gent
authors: David J
authors: DJ
authors: Chen
authors: Thomas
authors: T
authors: Perlmann
mesh_terms: D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair; D051747:DNA-Activated Protein Kinase / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D055786:Gene Knockout Techniques; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000503:physiopathology
chemical_list: C109198:CIB1 protein, human; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; C539882:NR4A2 protein, human; C539883:Nr4a2 protein, mouse; D009687:Nuclear Proteins; D057126:Nuclear Receptor Subfamily 4, Group A, Member 2; D051747:DNA-Activated Protein Kinase; C497264:Prkdc protein, mouse