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Autor(en) / Beteiligte

Titel

WRN helicase is a synthetic lethal target in microsatellite unstable cancers

Ist Teil von

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

Synthetic lethality-an interaction between two genetic events through which the co-occurrence of these two genetic events leads to cell death, but each event alone does not-can be exploited for cancer therapeutics . DNA repair processes represent attractive synthetic lethal targets, because many cancers exhibit an impairment of a DNA repair pathway, which can lead to dependence on specific repair proteins . The success of poly(ADP-ribose) polymerase 1 (PARP-1) inhibitors in cancers with deficiencies in homologous recombination highlights the potential of this approach . Hypothesizing that other DNA repair defects would give rise to synthetic lethal relationships, we queried dependencies in cancers with microsatellite instability (MSI), which results from deficient DNA mismatch repair. Here we analysed data from large-scale silencing screens using CRISPR-Cas9-mediated knockout and RNA interference, and found that the RecQ DNA helicase WRN was selectively essential in MSI models in vitro and in vivo, yet dispensable in models of cancers that are microsatellite stable. Depletion of WRN induced double-stranded DNA breaks and promoted apoptosis and cell cycle arrest selectively in MSI models. MSI cancer models required the helicase activity of WRN, but not its exonuclease activity. These findings show that WRN is a synthetic lethal vulnerability and promising drug target for MSI cancers.

Sprache: Englisch
Identifikatoren: ISSN: 0028-0836, 1476-4687
eISSN: 1476-4687
DOI: 10.1038/s41586-019-1102-x
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_6580861

Format: –
Schlagworte: Adenosine diphosphate, Analysis, Apoptosis, Apoptosis - genetics, Biomarkers, Cancer, Cell cycle, Cell Cycle Checkpoints - genetics, Cell death, Cell Line, Tumor, CRISPR, CRISPR-Cas Systems - genetics, CRISPR-Cas technology, Datasets, Deoxyribonucleic acid, Dependence, Depletion, DNA, DNA Breaks, Double-Stranded, DNA damage, DNA helicase, DNA repair, Exonuclease, Gene expression, Genetic research, Genomes, Helicases, Homologous recombination, Homology, Humans, Instability, Kinases, Lethality, Microsatellite Instability, Microsatellite Repeats - genetics, Mismatch repair, Models, Genetic, Mutation, Neoplasms - genetics, Neoplasms - pathology, Poly(ADP-ribose), Poly(ADP-ribose) polymerase, RecQ protein, Repair, Ribose, RNA Interference, RNA-mediated interference, Stability, Stability analysis, Synthetic biology, Synthetic Lethal Mutations - genetics, Tumor Suppressor Protein p53 - metabolism, Werner syndrome, Werner Syndrome Helicase - deficiency, Werner Syndrome Helicase - genetics

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