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

Janne J M van Schie, Atiq Faramarz, Jesper A Balk, Grant S Stewart, Erika Cantelli, Anneke B Oostra, Martin A Rooimans, Joanna L Parish, Cynthia de Almeida Estéves, Katja Dumic, Ingeborg Barisic, Karin E M Diderich, Marjon A van Slegtenhorst, Mohammad Mahtab, Francesca M Pisani, Hein Te Riele, Najim Ameziane, Rob M F Wolthuis, Job de Lange

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29 Citations (Scopus)


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 languageEnglish
Article number4287
Pages (from-to)4287
JournalNature communications
Issue number1
Publication statusPublished - 1 Dec 2020

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