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

Margaret E. Harley; Olga Murina; Andrea Leitch; Martin R. Higgs; Louise S Bicknell; Gökhan Yigit; Andrew N. Blackford; Anastasia Zlatanou; Karen J. Mackenzie; Kaalak Reddy; Mihail Halachev; Sarah McGlasson; Martin A M Reijns; Adeline Fluteau; Carol Anne Martin; Simone Sabbioneda; Nursel H. Elcioglu; Janine Altmüller; Holger Thiele; Lynn Greenhalgh; Luciana Chessa; Mohamad Maghnie; Mahmoud Salim; Michael B. Bober; Peter Nürnberg; Stephen P. Jackson; Matthew E. Hurles; Bernd Wollnik; Grant S. Stewart; Andrew P. Jackson

doi:10.1038/ng.3451

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

Margaret E. Harley, Olga Murina, Andrea Leitch, Martin R. Higgs, Louise S Bicknell, Gökhan Yigit, Andrew N. Blackford, Anastasia Zlatanou, Karen J. Mackenzie, Kaalak Reddy, Mihail Halachev, Sarah McGlasson, Martin A M Reijns, Adeline Fluteau, Carol Anne Martin, Simone Sabbioneda, Nursel H. Elcioglu, Janine Altmüller, Holger Thiele, Lynn GreenhalghLuciana Chessa, Mohamad Maghnie, Mahmoud Salim, Michael B. Bober, Peter Nürnberg, Stephen P. Jackson, Matthew E. Hurles, Bernd Wollnik, Grant S. Stewart, Andrew P. Jackson

Istituto "Giannina Gaslini"

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	36-43
Number of pages	8
Journal	Nature Genetics
Volume	48
Issue number	1
DOIs	https://doi.org/10.1038/ng.3451
Publication status	Published - Jan 2016

Keywords

Amino Acid Sequence
Cell Proliferation
Child, Preschool
DNA Damage
Dwarfism
Facies
Histones
Humans
Microcephaly
Molecular Sequence Data
Mutation
Phosphorylation
Replication Protein A
S Phase
Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
Ubiquitin-Protein Ligases
Ultraviolet Rays
Journal Article
Research Support, Non-U.S. Gov't

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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., ... Jackson, A. P. (2016). TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism. Nature Genetics, 48(1), 36-43. https://doi.org/10.1038/ng.3451

TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism. / Harley, Margaret E.; Murina, Olga; Leitch, Andrea; Higgs, Martin R.; Bicknell, Louise S; Yigit, Gökhan; Blackford, Andrew N.; Zlatanou, Anastasia; Mackenzie, Karen J.; Reddy, Kaalak; Halachev, Mihail; McGlasson, Sarah; Reijns, Martin A M; Fluteau, Adeline; Martin, Carol Anne; Sabbioneda, Simone; Elcioglu, Nursel H.; Altmüller, Janine; Thiele, Holger; Greenhalgh, Lynn; Chessa, Luciana; Maghnie, Mohamad; Salim, Mahmoud; Bober, Michael B.; Nürnberg, Peter; Jackson, Stephen P.; Hurles, Matthew E.; Wollnik, Bernd; Stewart, Grant S.; Jackson, Andrew P.

In: Nature Genetics, Vol. 48, No. 1, 01.2016, p. 36-43.

Research output: Contribution to journal › Article › peer-review

Harley, ME, Murina, O, Leitch, A, Higgs, MR, Bicknell, LS, Yigit, G, Blackford, AN, Zlatanou, A, Mackenzie, KJ, Reddy, K, Halachev, M, McGlasson, S, Reijns, MAM, Fluteau, A, Martin, CA, Sabbioneda, S, Elcioglu, NH, Altmüller, J, Thiele, H, Greenhalgh, L, Chessa, L, Maghnie, M, Salim, M, Bober, MB, Nürnberg, P, Jackson, SP, Hurles, ME, Wollnik, B, Stewart, GS & Jackson, AP 2016, 'TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism', Nature Genetics, vol. 48, no. 1, pp. 36-43. https://doi.org/10.1038/ng.3451

Harley, Margaret E. ; Murina, Olga ; Leitch, Andrea ; Higgs, Martin R. ; Bicknell, Louise S ; Yigit, Gökhan ; Blackford, Andrew N. ; Zlatanou, Anastasia ; Mackenzie, Karen J. ; Reddy, Kaalak ; Halachev, Mihail ; McGlasson, Sarah ; Reijns, Martin A M ; Fluteau, Adeline ; Martin, Carol Anne ; Sabbioneda, Simone ; Elcioglu, Nursel H. ; Altmüller, Janine ; Thiele, Holger ; Greenhalgh, Lynn ; Chessa, Luciana ; Maghnie, Mohamad ; Salim, Mahmoud ; Bober, Michael B. ; Nürnberg, Peter ; Jackson, Stephen P. ; Hurles, Matthew E. ; Wollnik, Bernd ; Stewart, Grant S. ; Jackson, Andrew P. / TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism. In: Nature Genetics. 2016 ; Vol. 48, No. 1. pp. 36-43.

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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.",

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AU - Greenhalgh, Lynn

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AU - Maghnie, Mohamad

AU - Salim, Mahmoud

AU - Bober, Michael B.

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

Abstract

Keywords

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