Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.26.5 (RNase P)
 1,348 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human WRN, a RecQ helicase encoded by the Werner syndrome gene, is implicated in genome maintenance, including replication, recombination, excision repair and DNA damage response. These genetic processes and expression of WRN are concomitantly upregulated in many types of cancers. Therefore, targeted destruction of this helicase could be useful for elimination of cancer cells. Here, we provide a proof of concept for applying the external guide sequence (EGS) approach in directing an RNase P RNA to efficiently cleave the WRN mRNA in cultured human cell lines, thus abolishing translation and activity of this distinctive 3'-5' DNA helicase-nuclease. Remarkably, EGS-directed knockdown of WRN leads to severe inhibition of cell viability. Hence, further assessment of this targeting system could be beneficial for selective cancer therapies, particularly in the light of the recent improvements introduced into EGSs.
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PMID:Targeted inhibition of WRN helicase by external guide sequence and RNase P RNA. 2680 8

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. Therefore, directed inhibition of this RecQ helicase could be beneficial to selective cancer therapy. Inhibition of WRN is feasible by the use of small-molecule inhibitors or application of RNA interference and EGS/RNase P targeting systems. Remarkably, helicase depletion leads to a severe reduction in cell viability due to mitotic catastrophe, which is triggered by replication stress induced by DNA repair failure and fork progression arrest. Moreover, we present new evidence that WRN depletion results in early changes of RNA polymerase III and RNase P activities, thereby implicating chromatin-associated tRNA enzymes in WRN-related stress response. Combined with the recently discovered roles of RecQ helicases in cancer, current data support the targeting prospect of these genome guardians, as a means of developing clinical phases aimed at diminishing adaptive resistance to present targeted therapies.
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PMID:Targeted inhibition of WRN helicase, replication stress and cancer. 2790 25