Targeted inhibition of WRN helicase by external guide sequence and RNase P RNA

Anna Hitrik; Ghada Abboud-Jarrous; Natalie Orlovetskie; Raphael Serruya; Nayef Jarrous

doi:10.1016/j.bbagrm.2016.01.004

Targeted inhibition of WRN helicase by external guide sequence and RNase P RNA

Anna Hitrik, Ghada Abboud-Jarrous, Natalie Orlovetskie, Raphael Serruya, Nayef Jarrous^*

^*Corresponding author for this work

Department of Microbiology and Molecular Genetics

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

Abstract

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.

Original language	American English
Pages (from-to)	572-580
Number of pages	9
Journal	Biochimica et Biophysica Acta - Gene Regulatory Mechanisms
Volume	1859
Issue number	4
DOIs	https://doi.org/10.1016/j.bbagrm.2016.01.004
State	Published - 1 Apr 2016

Bibliographical note

Funding Information:
We thank Dr. Tali Burstyn-Cohen (Hebrew University, Israel) for supporting the cell biology section of this research. We also thank Profs. Sidney Altman (Yale University, USA), Chang-En Yu (University of Washington, Seattle, Washington, USA) and Ram Reddy (Baylor College of Medicine, Houston, Texas, USA) for providing polyclonal antibodies directed against human RNase P, WRN cDNA and U6 snRNA gene, respectively. R. Serruya and N. Orlovetskie are grateful for doctoral fellowship support from the Hoffman Leadership and Responsibility Program and the Rudin Foundation, respectively. This research was supported by the Israel Cancer Association (grant # 2002-0048-B ) and the Israel Science Foundation (grant # 368/11 ).

Publisher Copyright:
© 2016 Elsevier B.V.

Keywords

External guide sequence
RNase P RNA
WRN helicase, selective cancer therapy
Werner syndrome

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.bbagrm.2016.01.004

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abstract = "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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author = "Anna Hitrik and Ghada Abboud-Jarrous and Natalie Orlovetskie and Raphael Serruya and Nayef Jarrous",

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Targeted inhibition of WRN helicase by external guide sequence and RNase P RNA

Abstract

Bibliographical note

Keywords

UN SDGs

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