Warsaw Breakage Syndrome associated DDX11 helicase resolves G-quadruplex structures to support sister chromatid cohesion.
Abnormalities, Multiple
/ etiology
Cell Proliferation
DEAD-box RNA Helicases
/ chemistry
DNA Helicases
/ chemistry
Fanconi Anemia Complementation Group Proteins
/ genetics
G-Quadruplexes
Humans
Male
Middle Aged
Mutation, Missense
Protein Stability
Pseudogenes
RNA Helicases
/ genetics
Rad51 Recombinase
/ genetics
Sister Chromatid Exchange
Syndrome
Tumor Suppressor Protein p53
/ genetics
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
27 08 2020
27 08 2020
Historique:
received:
20
12
2019
accepted:
30
07
2020
entrez:
29
8
2020
pubmed:
29
8
2020
medline:
25
9
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32855419
doi: 10.1038/s41467-020-18066-8
pii: 10.1038/s41467-020-18066-8
pmc: PMC7452896
doi:
Substances chimiques
Fanconi Anemia Complementation Group Proteins
0
TP53 protein, human
0
Tumor Suppressor Protein p53
0
RAD51 protein, human
EC 2.7.7.-
Rad51 Recombinase
EC 2.7.7.-
DNA Helicases
EC 3.6.4.-
BRIP1 protein, human
EC 3.6.4.13
DDX11 protein, human
EC 3.6.4.13
DEAD-box RNA Helicases
EC 3.6.4.13
RNA Helicases
EC 3.6.4.13
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4287Subventions
Organisme : Medical Research Council
ID : MR/R022011/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/T015985/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C17183/A23303
Pays : United Kingdom
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