Please use this identifier to cite or link to this item: http://hdl.handle.net/2381/45543
Full metadata record
DC FieldValueLanguage
dc.contributor.authorMunnur, D-
dc.contributor.authorSomers, J-
dc.contributor.authorSkalka, G-
dc.contributor.authorWeston, R-
dc.contributor.authorJukes-Jones, R-
dc.contributor.authorBhogadia, M-
dc.contributor.authorDominguez, C-
dc.contributor.authorCain, K-
dc.contributor.authorAhel, I-
dc.contributor.authorMalewicz, M-
dc.date.accessioned2019-09-10T13:37:49Z-
dc.date.available2019-09-10T13:37:49Z-
dc.date.issued2019-02-19-
dc.identifier.citationCell Reports, 2019, 26 (8), pp. 2028-2036.e6en
dc.identifier.urihttps://www.sciencedirect.com/science/article/pii/S2211124719301123?via%3Dihuben
dc.identifier.urihttp://hdl.handle.net/2381/45543-
dc.descriptionSupplemental Information includes four figures and one table and can be found with this article online at https://doi.org/10.1016/j.celrep.2019.01.083.en
dc.description.abstractAlthough poly-ADP-ribosylation (PARylation) of DNA repair factors had been well documented, its role in the repair of DNA double-strand breaks (DSBs) is poorly understood. NR4A nuclear orphan receptors were previously linked to DSB repair; however, their function in the process remains elusive. Classically, NR4As function as transcription factors using a specialized tandem zinc-finger DNA-binding domain (DBD) for target gene induction. Here, we show that NR4A DBD is bi-functional and can bind poly-ADP-ribose (PAR) through a pocket localized in the second zinc finger. Separation-of-function mutants demonstrate that NR4A PAR binding, while dispensable for transcriptional activity, facilitates repair of radiation-induced DNA double-strand breaks in G1. Moreover, we define DNA-PKcs protein as a prominent target of ionizing radiation-induced PARylation. Mechanistically, NR4As function by directly targeting poly-ADP-ribosylated DNA-PKcs to facilitate its autophosphorylation-promoting DNA-PK kinase assembly at DNA lesions. Selective targeting of the PAR-binding pocket of NR4A presents an opportunity for cancer therapy.en
dc.description.sponsorshipMRC (Medical Research Council, UK) funds M.M.’s work. We thank Dr. Thomas Perlmann (Karolinska Institute, Stockholm, Sweden) for sharing plasmids and antibodies. We also thank Dr. Robert Haché (Ottawa, Canada) for sharing the EGFP-Ku70 expression construct. Dr. Tom Misteli (NIH, USA) is acknowledged for sharing the mCherry-LacI plasmid. We thank Dr. Benjamin Chen (UT Southwestern, USA) for providing I-SceI expression vector. We thank Dr. Kate Dudek for the microarray analysis.en
dc.language.isoenen
dc.publisherElsevier (Cell Press)en
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/30784586-
dc.rightsCopyright © the authors, 2019. This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.subjectDNA repairen
dc.subjectDNA-PKen
dc.subjectDSBen
dc.subjectNHEJen
dc.subjectNR4Aen
dc.subjectPARPen
dc.subjectdouble-strand breaksen
dc.subjectnon-homologous end joiningen
dc.subjectpoly-ADP-riboseen
dc.subjecttranscription factorsen
dc.titleNR4A Nuclear Receptors Target Poly-ADP-Ribosylated DNA-PKcs Protein to Promote DNA Repair.en
dc.typeJournal Articleen
dc.identifier.doi10.1016/j.celrep.2019.01.083-
dc.identifier.eissn2211-1247-
dc.identifier.piiS2211-1247(19)30112-3-
dc.description.statusPeer-revieweden
dc.description.versionPublisher Versionen
dc.type.subtypeJournal Article-
pubs.organisational-group/Organisationen
pubs.organisational-group/Organisation/COLLEGE OF LIFE SCIENCESen
pubs.organisational-group/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciencesen
pubs.organisational-group/Organisation/COLLEGE OF LIFE SCIENCES/Biological Sciences/Molecular & Cell Biologyen
dc.dateaccepted2019-01-23-
Appears in Collections:Published Articles, Dept. of Molecular and Cell Biology

Files in This Item:
File Description SizeFormat 
1-s2.0-S2211124719301123-main.pdfPublished (publisher PDF)3.36 MBAdobe PDFView/Open


Items in LRA are protected by copyright, with all rights reserved, unless otherwise indicated.