Genetic interactions of G-quadruplexes in humans.
G-quadruplex
G-quadruplex ligands
G4
biochemistry
cancer
chemical biology
chromosomes
gene expression
genetic vulnerability
human
nucleic acid structure
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
09 07 2019
09 07 2019
Historique:
received:
12
03
2019
accepted:
17
06
2019
entrez:
10
7
2019
pubmed:
10
7
2019
medline:
26
2
2020
Statut:
epublish
Résumé
G-quadruplexes (G4) are alternative nucleic acid structures involved in transcription, translation and replication. Aberrant G4 formation and stabilisation is linked to genome instability and cancer. G4 ligand treatment disrupts key biological processes leading to cell death. To discover genes and pathways involved with G4s and gain mechanistic insights into G4 biology, we present the first unbiased genome-wide study to systematically identify human genes that promote cell death when silenced by shRNA in the presence of G4-stabilising small molecules. Many novel genetic vulnerabilities were revealed opening up new therapeutic possibilities in cancer, which we exemplified by an orthogonal pharmacological inhibition approach that phenocopies gene silencing. We find that targeting the WEE1 cell cycle kinase or USP1 deubiquitinase in combination with G4 ligand treatment enhances cell killing. We also identify new genes and pathways regulating or interacting with G4s and demonstrate that the DDX42 DEAD-box helicase is a newly discovered G4-binding protein.
Identifiants
pubmed: 31287417
doi: 10.7554/eLife.46793
pii: 46793
pmc: PMC6615864
doi:
pii:
Substances chimiques
Ligands
0
Neoplasm Proteins
0
RNA, Small Interfering
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Royal Society
ID : RP130039
Pays : International
Organisme : Wellcome
ID : 209441/z/17/z
Pays : International
Organisme : Pew Charitable Trusts
ID : 00028354
Pays : International
Organisme : Cancer Research UK
ID : C14303/A17197
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C9681/A18618
Pays : United Kingdom
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A21143
Pays : United Kingdom
Informations de copyright
© 2019, Zyner et al.
Déclaration de conflit d'intérêts
KZ, DM, SA, SM, MD, NE, DT No competing interests declared, GH Is associated with transOMIC Technologies, who have commercialised libraries constructed using the shERWOOD and ultramiR design strategies. SB Is founder, adviser and shareholder of Cambridge Epigenetix Ltd.
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