TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism

Harley, M.E.; Murina, O.; Leitch, A.; Higgs, M.R.; Bicknell, L.S.; Yigit, G.; Blackford, A.N.; Zlatanou, A.; Mackenzie, K.J.; Reddy, K.; Halachev, M.; McGlasson, S.; Reijns, M.A.M.; Fluteau, A.; Martin, C.A.; Sabbioneda, S.; Elcioglu, N.H.; Altmüller, J.; Thiele, H.; Greenhalgh, L.; Chessa, L.; Maghnie, M.; Salim, M.; Bober, M.B.; Nürnberg, P.; Jackson, S.P.; Hurles, M.E.; Wollnik, B.; Stewart, G.S.; Jackson, A.P.

TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism

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Item Type:	Article
Title:	TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism
Creators Name:	Harley, M.E., Murina, O., Leitch, A., Higgs, M.R., Bicknell, L.S., Yigit, G., Blackford, A.N., Zlatanou, A., Mackenzie, K.J., Reddy, K., Halachev, M., McGlasson, S., Reijns, M.A.M., Fluteau, A., Martin, C.A., Sabbioneda, S., Elcioglu, N.H., Altmüller, J., Thiele, H., Greenhalgh, L., Chessa, L., Maghnie, M., Salim, M., Bober, M.B., Nürnberg, P., Jackson, S.P., Hurles, M.E., Wollnik, B., Stewart, G.S. and Jackson, A.P.
Abstract:	DNA lesions encountered by replicative polymerases threaten genome stability and cell cycle progression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitin ligase, in patients with microcephalic primordial dwarfism. We establish that TRAIP relocalizes to sites of DNA damage, where it is required for optimal phosphorylation of H2AX and RPA2 during S-phase in response to ultraviolet (UV) irradiation, as well as fork progression through UV-induced DNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP therefore limit cellular proliferation, providing a potential mechanism for microcephaly and dwarfism phenotypes. Human genetics thus identifies TRAIP as a component of the DNA damage response to replication-blocking DNA lesions.
Keywords:	Amino Acid Sequence, Cell Proliferation, DNA Damage, Dwarfism, Facies, Histones, Microcephaly, Molecular Sequence Data, Mutation, Phosphorylation, Replication Protein A, S Phase, Tumor Necrosis Factor Receptor-Associated Peptides and Proteins, Ubiquitin-Protein Ligases, Ultraviolet Rays, Substances
Source:	Nature Genetics
ISSN:	1061-4036
Publisher:	Nature Publishing Group
Volume:	48
Number:	1
Page Range:	36-43
Date:	January 2016
Additional Information:	Copyright © 2016 Nature America, Inc. All rights reserved.
Official Publication:	https://doi.org/10.1038/ng.3451
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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