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

Janne J. M. Schie, Atiq Faramarz, Jesper A. Balk, Grant S. Stewart, Erika Cantelli, Anneke B. Oostra, Martin A. Rooimans, Joanna L. Parish, Cynthia Almeida Estéves, Katja Dumic, Ingeborg Barisic, Karin E. M. Diderich, Marjon A. Slegtenhorst, Mohammad Mahtab, Francesca M. Pisani, Hein Riele, Najim Ameziane, Rob M. F. Wolthuis () and Job Lange ()
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Janne J. M. Schie: Section of Oncogenetics, Cancer Center Amsterdam and Department of Clinical Genetics, Amsterdam University Medical Centers
Atiq Faramarz: Section of Oncogenetics, Cancer Center Amsterdam and Department of Clinical Genetics, Amsterdam University Medical Centers
Jesper A. Balk: Section of Oncogenetics, Cancer Center Amsterdam and Department of Clinical Genetics, Amsterdam University Medical Centers
Grant S. Stewart: Institute of Cancer and Genomic Sciences, University of Birmingham
Erika Cantelli: Netherlands Cancer Institute, Division of Tumor Biology and Immunology
Anneke B. Oostra: Section of Oncogenetics, Cancer Center Amsterdam and Department of Clinical Genetics, Amsterdam University Medical Centers
Martin A. Rooimans: Section of Oncogenetics, Cancer Center Amsterdam and Department of Clinical Genetics, Amsterdam University Medical Centers
Joanna L. Parish: Institute of Cancer and Genomic Sciences, University of Birmingham
Cynthia Almeida Estéves: Hospital Militar
Katja Dumic: University Hospital Centre Zagreb, University of Zagreb Medical School
Ingeborg Barisic: Children’s Hospital Zagreb, Center of Excellence for Reproductive and Regenerative Medicine, Medical School University of Zagreb
Karin E. M. Diderich: Erasmus Medical Center
Marjon A. Slegtenhorst: Erasmus Medical Center
Mohammad Mahtab: Istituto di Biochimica e Biologia Cellulare, Consiglio Nazionale delle Ricerche
Francesca M. Pisani: Istituto di Biochimica e Biologia Cellulare, Consiglio Nazionale delle Ricerche
Hein Riele: Netherlands Cancer Institute, Division of Tumor Biology and Immunology
Najim Ameziane: Section of Oncogenetics, Cancer Center Amsterdam and Department of Clinical Genetics, Amsterdam University Medical Centers
Rob M. F. Wolthuis: Section of Oncogenetics, Cancer Center Amsterdam and Department of Clinical Genetics, Amsterdam University Medical Centers
Job Lange: Section of Oncogenetics, Cancer Center Amsterdam and Department of Clinical Genetics, Amsterdam University Medical Centers

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18066-8

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