微卫星不稳定性
基因组不稳定性
解旋酶
生物
遗传学
DNA错配修复
DNA修复
DNA损伤
DNA
DNA复制
三核苷酸重复扩增
沃纳综合征
微卫星
分子生物学
癌症研究
基因
核糖核酸
等位基因
作者
Edmond M. Chan,Kyla Foster,Adam J. Bass
出处
期刊:Cancer treatment and research
日期:2023-01-01
卷期号:: 313-328
标识
DOI:10.1007/978-3-031-30065-3_17
摘要
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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