WRN Is a Promising Synthetic Lethal Target for Cancers with Microsatellite Instability (MSI).
Cancer Treat Res
; 186: 313-328, 2023.
Article
em En
| MEDLINE
| ID: mdl-37978143
ABSTRACT
Microsatellite instability (MSI), a type of genetic hypermutability arising from impaired DNA mismatch repair (MMR), is observed in approximately 3% of all cancers. Preclinical work has identified the RecQ helicase WRN as a promising synthetic lethal target for patients with MSI cancers. WRN depletion substantially impairs the viability of MSI, but not microsatellite stable (MSS), cells. Experimental evidence suggests that this synthetic lethal phenotype is driven by numerous TA dinucleotide repeats that undergo expansion mutations in the setting of long-standing MMR deficiency. The lengthening of TA repeats increases their propensity to form secondary DNA structures that require WRN to resolve. In the absence of WRN helicase activity, these unresolved DNA secondary structures stall DNA replication forks and induce catastrophic DNA damage.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Colorretais
/
Instabilidade de Microssatélites
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article