The Werner syndrome helicase (WRN) is an ATP-dependent helicase with 3' to 5' DNA exonuclease activity that regulates the replicative potential of dividing cells, and WRN loss-of-function mutations promote cellular senescence and neoplastic transformation[2]. WRN helicase has several roles in genome maintenance, such as replication, base excision repair, recombination, DNA damage response and transcription. These processes are often found upregulated in human cancers, many of which display increased levels of WRN[3]. WRN depletion in HeLa cells attenuates global protein synthesis without affecting the level of key components of the mRNA export machinery. WRN depletion affects the nuclear export of mRNAs and demonstrated that WRN interacts with mRNA and the Nuclear RNA Export Factor 1 (NXF1)[4]. NSC617145 is a WRN helicase inhibitor. In FA-D2(-/-) cells, NSC 617145 acted synergistically with very low concentrations of mitomycin C to inhibit proliferation in a WRN-dependent manner and induce double-strand breaks (DSB) and chromosomal abnormalities. Under these conditions, ataxia-telangiectasia mutated activation and accumulation of DNA-dependent protein kinase, catalytic subunit pS2056 foci suggested an increased number of DSBs processed by nonhomologous end-joining (NHEJ). Rad51 foci were also elevated in FA-D2(-/-) cells exposed to NSC 617145 and mitomycin C, suggesting that WRN helicase inhibition interferes with later steps of homologous recombination at ICL-induced DSBs[5].
NSC 617145 细胞实验
Cell Line
Concentration
Treated Time
Description
References
U2OS cells
1.5 µM
2 days
NSC 617145 inhibits cell proliferation, independent of p53 status
Cancer Res. 2013 Sep 1;73(17):5497-507
HeLa cells
1.5 µM
3 days
NSC 617145 inhibits cell proliferation in a WRN-dependent manner
Cancer Res. 2013 Sep 1;73(17):5497-507
MO59J cells
0.5 µM
3 days
WRN helicase inhibition in cells deficient in both FA and NHEJ pathways further compromises their ability to proliferate
Cell Cycle. 2013 Oct 15;12(20):3329-35
MO59K cells
0.5 µM
3 days
WRN helicase inhibition causes greater genomic instability when NHEJ is operational
Cell Cycle. 2013 Oct 15;12(20):3329-35
Human endocervical carcinoma cells
0.5 µM
3 days
Inhibition of WRN helicase activity, resulting in decreased cell proliferation and accumulation of DNA damage and chromosomal abnormalities
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