Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion

Janne van Schie; Atiq Faramarz; Jesper Balk; Grant Stewart; Erika Cantelli; Anneke Oostra; Martin Rooimans; Joanna Parish; Cynthia de Almeida Esteves; Katja Dumic; Ingeborg Barisic; Karin Diderich; Marjon van Slegtenhorst; Mohammad Mahtab; Francesca Pisani; Hein te Riele; Najim Ameziane; Rob Wolthuis; Job de Lange

doi:10.1038/s41467-020-18066-8

Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion

Janne van Schie, Atiq Faramarz, Jesper Balk, Grant Stewart, Erika Cantelli, Anneke Oostra, Martin Rooimans, Joanna Parish, Cynthia de Almeida Esteves, Katja Dumic, Ingeborg Barisic, Karin Diderich, Marjon van Slegtenhorst, Mohammad Mahtab, Francesca Pisani, Hein te Riele, Najim Ameziane, Rob Wolthuis, Job de Lange

Cancer and Genomic Sciences

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Abstract

Warsaw Breakage Syndrome (WABS) is a rare disorder related to cohesinopathies and Fanconi anemia, caused by bi-allelic mutations in DDX11. Here, we report multiple compound heterozygous WABS cases, each displaying destabilized DDX11 protein and residual DDX11 function at the cellular level. Patient-derived cell lines exhibit sensitivity to topoisomerase and PARP inhibitors, defective sister chromatid cohesion and reduced DNA replication fork speed. Deleting DDX11 in RPE1-TERT cells inhibits proliferation and survival in a TP53-dependent manner and causes chromosome breaks and cohesion defects, independent of the expressed pseudogene DDX12p. Importantly, G-quadruplex (G4) stabilizing compounds induce chromosome breaks and cohesion defects which are strongly aggravated by inactivation of DDX11 but not FANCJ. The DNA helicase domain of DDX11 is essential for sister chromatid cohesion and resistance to G4 stabilizers. We propose that DDX11 is a DNA helicase protecting against G4 induced double-stranded breaks and concomitant loss of cohesion, possibly at DNA replication forks.

Original language	English
Article number	4287
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-18066-8
Publication status	Published - 27 Aug 2020

Bibliographical note

M1 - 4287

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-020-18066-8Licence: Creative Commons: Attribution (CC BY)

vanSchieJ2020Warsaw
van Schie, J.J.M., Faramarz, A., Balk, J.A. et al. Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion. Nat Commun 11, 4287 (2020). https://doi.org/10.1038/s41467-020-18066-8
Final published version, 4.02 MBLicence: Creative Commons: Attribution (CC BY)

https://doi.org/10.1038/s41467-020-18066-8Licence: Creative Commons: Attribution (CC BY)

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van Schie, J., Faramarz, A., Balk, J., Stewart, G., Cantelli, E., Oostra, A., Rooimans, M., Parish, J., de Almeida Esteves, C., Dumic, K., Barisic, I., Diderich, K., van Slegtenhorst, M., Mahtab, M., Pisani, F., te Riele, H., Ameziane, N., Wolthuis, R., & de Lange, J. (2020). Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion. Nature Communications, 11(1), Article 4287. https://doi.org/10.1038/s41467-020-18066-8

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title = "Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion",

abstract = "Warsaw Breakage Syndrome (WABS) is a rare disorder related to cohesinopathies and Fanconi anemia, caused by bi-allelic mutations in DDX11. Here, we report multiple compound heterozygous WABS cases, each displaying destabilized DDX11 protein and residual DDX11 function at the cellular level. Patient-derived cell lines exhibit sensitivity to topoisomerase and PARP inhibitors, defective sister chromatid cohesion and reduced DNA replication fork speed. Deleting DDX11 in RPE1-TERT cells inhibits proliferation and survival in a TP53-dependent manner and causes chromosome breaks and cohesion defects, independent of the expressed pseudogene DDX12p. Importantly, G-quadruplex (G4) stabilizing compounds induce chromosome breaks and cohesion defects which are strongly aggravated by inactivation of DDX11 but not FANCJ. The DNA helicase domain of DDX11 is essential for sister chromatid cohesion and resistance to G4 stabilizers. We propose that DDX11 is a DNA helicase protecting against G4 induced double-stranded breaks and concomitant loss of cohesion, possibly at DNA replication forks.",

author = "{van Schie}, Janne and Atiq Faramarz and Jesper Balk and Grant Stewart and Erika Cantelli and Anneke Oostra and Martin Rooimans and Joanna Parish and {de Almeida Esteves}, Cynthia and Katja Dumic and Ingeborg Barisic and Karin Diderich and {van Slegtenhorst}, Marjon and Mohammad Mahtab and Francesca Pisani and {te Riele}, Hein and Najim Ameziane and Rob Wolthuis and {de Lange}, Job",

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van Schie, J, Faramarz, A, Balk, J, Stewart, G, Cantelli, E, Oostra, A, Rooimans, M, Parish, J, de Almeida Esteves, C, Dumic, K, Barisic, I, Diderich, K, van Slegtenhorst, M, Mahtab, M, Pisani, F, te Riele, H, Ameziane, N, Wolthuis, R & de Lange, J 2020, 'Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion', Nature Communications, vol. 11, no. 1, 4287. https://doi.org/10.1038/s41467-020-18066-8

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T1 - Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion

AU - van Schie, Janne

AU - Faramarz, Atiq

AU - Balk, Jesper

AU - Stewart, Grant

AU - Cantelli, Erika

AU - Oostra, Anneke

AU - Rooimans, Martin

AU - Parish, Joanna

AU - de Almeida Esteves, Cynthia

AU - Dumic, Katja

AU - Barisic, Ingeborg

AU - Diderich, Karin

AU - van Slegtenhorst, Marjon

AU - Mahtab, Mohammad

AU - Pisani, Francesca

AU - te Riele, Hein

AU - Ameziane, Najim

AU - Wolthuis, Rob

AU - de Lange, Job

N1 - M1 - 4287

PY - 2020/8/27

Y1 - 2020/8/27

N2 - Warsaw Breakage Syndrome (WABS) is a rare disorder related to cohesinopathies and Fanconi anemia, caused by bi-allelic mutations in DDX11. Here, we report multiple compound heterozygous WABS cases, each displaying destabilized DDX11 protein and residual DDX11 function at the cellular level. Patient-derived cell lines exhibit sensitivity to topoisomerase and PARP inhibitors, defective sister chromatid cohesion and reduced DNA replication fork speed. Deleting DDX11 in RPE1-TERT cells inhibits proliferation and survival in a TP53-dependent manner and causes chromosome breaks and cohesion defects, independent of the expressed pseudogene DDX12p. Importantly, G-quadruplex (G4) stabilizing compounds induce chromosome breaks and cohesion defects which are strongly aggravated by inactivation of DDX11 but not FANCJ. The DNA helicase domain of DDX11 is essential for sister chromatid cohesion and resistance to G4 stabilizers. We propose that DDX11 is a DNA helicase protecting against G4 induced double-stranded breaks and concomitant loss of cohesion, possibly at DNA replication forks.

AB - Warsaw Breakage Syndrome (WABS) is a rare disorder related to cohesinopathies and Fanconi anemia, caused by bi-allelic mutations in DDX11. Here, we report multiple compound heterozygous WABS cases, each displaying destabilized DDX11 protein and residual DDX11 function at the cellular level. Patient-derived cell lines exhibit sensitivity to topoisomerase and PARP inhibitors, defective sister chromatid cohesion and reduced DNA replication fork speed. Deleting DDX11 in RPE1-TERT cells inhibits proliferation and survival in a TP53-dependent manner and causes chromosome breaks and cohesion defects, independent of the expressed pseudogene DDX12p. Importantly, G-quadruplex (G4) stabilizing compounds induce chromosome breaks and cohesion defects which are strongly aggravated by inactivation of DDX11 but not FANCJ. The DNA helicase domain of DDX11 is essential for sister chromatid cohesion and resistance to G4 stabilizers. We propose that DDX11 is a DNA helicase protecting against G4 induced double-stranded breaks and concomitant loss of cohesion, possibly at DNA replication forks.

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U2 - 10.1038/s41467-020-18066-8

DO - 10.1038/s41467-020-18066-8

M3 - Article

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4287

ER -

Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion

Abstract

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