1. Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion
- Author
-
Najim Ameziane, Francesca M. Pisani, Erika Cantelli, Joanna L Parish, Job de Lange, Atiq Faramarz, Marjon van Slegtenhorst, Ingeborg Barišić, Jesper A. Balk, Grant S. Stewart, Martin A. Rooimans, Janne J. M. van Schie, Rob M. F. Wolthuis, Katja Dumic, Hein te Riele, Karin E. M. Diderich, Cynthia de Almeida Estéves, Anneke B. Oostra, Mohammad Mahtab, Clinical Genetics, Oral and Maxillofacial Surgery, Other Research, and Human genetics
- Subjects
Male ,0301 basic medicine ,DDX11 ,General Physics and Astronomy ,02 engineering and technology ,medicine.disease_cause ,DEAD-box RNA Helicases ,DNA repair enzymes ,Genetics ,DNA damage and repair ,DNA synthesis ,Cohesinopathies ,lcsh:Science ,Mutation ,Multidisciplinary ,biology ,G-quadruplex ,Protein Stability ,Chemistry ,Syndrome ,Middle Aged ,021001 nanoscience & nanotechnology ,Fanconi Anemia Complementation Group Proteins ,Cell biology ,Establishment of sister chromatid cohesion ,0210 nano-technology ,Pseudogenes ,RNA Helicases ,DNA repair ,Science ,Mutation, Missense ,Sister chromatid exchange ,DNA helicase ,DNA replication ,Article ,General Biochemistry, Genetics and Molecular Biology ,Warsaw breakage syndrome ,03 medical and health sciences ,medicine ,Humans ,Abnormalities, Multiple ,Cell Proliferation ,Topoisomerase ,DNA Helicases ,Helicase ,General Chemistry ,DNA Replication Fork ,G-Quadruplexes ,030104 developmental biology ,biology.protein ,lcsh:Q ,Rad51 Recombinase ,Tumor Suppressor Protein p53 ,Sister Chromatid Exchange - 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., 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.
- Published
- 2020
- Full Text
- View/download PDF