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

Margaret E Harley; Olga Murina; Andrea Leitch; Martin Higgs; Louise S Bicknell; Goekhan Yigit; Andrew 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 Altmuller; Holger Thiele; Lynn Greenhalgh; Luciana Chessa; Mohamad Maghnie; Mahmoud Salim; Michael B Bober; Peter Nurnberg; 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 Higgs, Louise S Bicknell, Goekhan Yigit, Andrew 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 Altmuller, Holger Thiele, Lynn GreenhalghLuciana Chessa, Mohamad Maghnie, Mahmoud Salim, Michael B Bober, Peter Nurnberg, Stephen P Jackson, Matthew E Hurles, Bernd Wollnik, Grant S Stewart, Andrew P Jackson

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/Seckel syndrome. 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 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 novel 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
Early online date	23 Nov 2015
DOIs	https://doi.org/10.1038/ng.3451
Publication status	Published - Jan 2016

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10.1038/ng.3451

TRAIP promotes DNA damage response during genome replication
This is the author's peer-reviewed manuscript as acceped for publication
Accepted author manuscript, 3.78 MB

HumGenSize
Jackson, A. (Principal Investigator)
EU government bodies
1/11/12 → 31/07/18
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Andrew Jackson
- andrew.jacksonigmm.ed.acuk
- MRC Human Genetics Unit - Programme Leader
- Edinburgh Neuroscience
- Institute of Genetics and Cancer
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Harley, M. E., Murina, O., Leitch, A., Higgs, M., Bicknell, L. S., Yigit, G., Blackford, A., 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., Altmuller, 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

@article{17af8c2e77c14d6dae6c88833df8c6b1,

title = "TRAIP promotes DNA damage response during genome replication and is mutated in primordial dwarfism",

abstract = "DNA lesions encountered by replicative polymerases threaten genome stability and cell cycleprogression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitinligase, in patients with microcephalic primordial dwarfism/Seckel syndrome. We establish that TRAIPrelocalizes to sites of DNA damage where it is required for optimal phosphorylation of H2AX andRPA2 during S-phase in response to UV irradiation, as well as fork progression through UV-inducedDNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP thereforelimit cellular proliferation, providing a potential mechanism for microcephaly and dwarfismphenotypes. Human genetics thus identifies TRAIP as a novel component of the DNA damageresponse to replication-blocking DNA lesions.",

author = "Harley, {Margaret E} and Olga Murina and Andrea Leitch and Martin Higgs and Bicknell, {Louise S} and Goekhan Yigit and Andrew Blackford and Anastasia Zlatanou and Mackenzie, {Karen J} and Kaalak Reddy and Mihail Halachev and Sarah McGlasson and Reijns, {Martin A M} and Adeline Fluteau and Carol-Anne Martin and Simone Sabbioneda and Elcioglu, {Nursel H} and Janine Altmuller and Holger Thiele and Lynn Greenhalgh and Luciana Chessa and Mohamad Maghnie and Mahmoud Salim and Bober, {Michael B} and Peter Nurnberg and Jackson, {Stephen P} and Hurles, {Matthew E} and Bernd Wollnik and Stewart, {Grant S} and Jackson, {Andrew P}",

note = "Date of Acceptance 25/09/2015",

year = "2016",

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doi = "10.1038/ng.3451",

language = "English",

volume = "48",

pages = "36--43",

journal = "Nature Genetics",

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Harley, ME, Murina, O, Leitch, A, Higgs, M, Bicknell, LS, Yigit, G, Blackford, A, Zlatanou, A, Mackenzie, KJ, Reddy, K, Halachev, M , McGlasson, S , Reijns, MAM, Fluteau, A, Martin, C-A, Sabbioneda, S, Elcioglu, NH, Altmuller, J, Thiele, H, Greenhalgh, L, Chessa, L, Maghnie, M, Salim, M, Bober, MB, Nurnberg, 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

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AU - Harley, Margaret E

AU - Murina, Olga

AU - Leitch, Andrea

AU - Higgs, Martin

AU - Bicknell, Louise S

AU - Yigit, Goekhan

AU - Blackford, Andrew

AU - Zlatanou, Anastasia

AU - Mackenzie, Karen J

AU - Reddy, Kaalak

AU - Halachev, Mihail

AU - McGlasson, Sarah

AU - Reijns, Martin A M

AU - Fluteau, Adeline

AU - Martin, Carol-Anne

AU - Sabbioneda, Simone

AU - Elcioglu, Nursel H

AU - Altmuller, Janine

AU - Thiele, Holger

AU - Greenhalgh, Lynn

AU - Chessa, Luciana

AU - Maghnie, Mohamad

AU - Salim, Mahmoud

AU - Bober, Michael B

AU - Nurnberg, Peter

AU - Jackson, Stephen P

AU - Hurles, Matthew E

AU - Wollnik, Bernd

AU - Stewart, Grant S

AU - Jackson, Andrew P

N1 - Date of Acceptance 25/09/2015

PY - 2016/1

Y1 - 2016/1

N2 - DNA lesions encountered by replicative polymerases threaten genome stability and cell cycleprogression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitinligase, in patients with microcephalic primordial dwarfism/Seckel syndrome. We establish that TRAIPrelocalizes to sites of DNA damage where it is required for optimal phosphorylation of H2AX andRPA2 during S-phase in response to UV irradiation, as well as fork progression through UV-inducedDNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP thereforelimit cellular proliferation, providing a potential mechanism for microcephaly and dwarfismphenotypes. Human genetics thus identifies TRAIP as a novel component of the DNA damageresponse to replication-blocking DNA lesions.

AB - DNA lesions encountered by replicative polymerases threaten genome stability and cell cycleprogression. Here we report the identification of mutations in TRAIP, encoding an E3 RING ubiquitinligase, in patients with microcephalic primordial dwarfism/Seckel syndrome. We establish that TRAIPrelocalizes to sites of DNA damage where it is required for optimal phosphorylation of H2AX andRPA2 during S-phase in response to UV irradiation, as well as fork progression through UV-inducedDNA lesions. TRAIP is necessary for efficient cell cycle progression and mutations in TRAIP thereforelimit cellular proliferation, providing a potential mechanism for microcephaly and dwarfismphenotypes. Human genetics thus identifies TRAIP as a novel component of the DNA damageresponse to replication-blocking DNA lesions.

U2 - 10.1038/ng.3451

DO - 10.1038/ng.3451

M3 - Article

SN - 1061-4036

VL - 48

SP - 36

EP - 43

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

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

Abstract

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