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

• Published in: Nature communications Vol. 11; no. 1; p. 4287
• Main Authors: van Schie, Janne J. M., Faramarz, Atiq, Balk, Jesper A., Stewart, Grant S., Cantelli, Erika, Oostra, Anneke B., Rooimans, Martin A., Parish, Joanna L., de Almeida Estéves, Cynthia, Dumic, Katja, Barisic, Ingeborg, Diderich, Karin E. M., van Slegtenhorst, Marjon A., Mahtab, Mohammad, Pisani, Francesca M., te Riele, Hein, Ameziane, Najim, Wolthuis, Rob M. F., de Lange, Job
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.08.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/109; 13/44; 13/89; 14/63; 38/23; 38/35; 38/71; 631/208; 631/337/1427; 631/337/151/1431; 631/45/607/1159; Anemia; Cell lines; Cell proliferation; Chromosomes; Cohesion; Deactivation; Defects; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA helicase; Fanconi syndrome; Humanities and Social Sciences; Inactivation; multidisciplinary; Mutation; p53 Protein; Poly(ADP-ribose) polymerase; Replication; Replication forks; Science; Science (multidisciplinary); Yeast
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-18066-8

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. WABS patient derived cells display loss of sister chromatid cohesion. Here the authors by analyzing WABS patient derived cells, reveal a role of the DDX11 helicase in resolving G-Quadruplex structures to support sister chromatid cohesion.