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Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells

Andrea E. Murmann, Quan Q. Gao, William Putzbach, Monal Patel, Elizabeth T. Bartom, Calvin Law, Bryan Bridgeman, Siquan Chen, Kaylin M. McMahon, C. Shad Thaxton, View ORCID ProfileMarcus E. Peter
doi: https://doi.org/10.1101/247429
Andrea E. Murmann
1Division of Hematology/Oncology
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  • For correspondence: m-peter@northwestern.edu amurmann@northwestern.edu
Quan Q. Gao
1Division of Hematology/Oncology
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William Putzbach
1Division of Hematology/Oncology
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Monal Patel
1Division of Hematology/Oncology
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Elizabeth T. Bartom
2Department of Biochemistry and Molecular Genetics
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Calvin Law
1Division of Hematology/Oncology
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Bryan Bridgeman
1Division of Hematology/Oncology
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Siquan Chen
7Cellular Screening Center, Institute for Genomics & Systems Biology, The University of Chicago, Chicago, IL 60637
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Kaylin M. McMahon
3Department of Urology
5Simpson Querrey Institute (SQI) for BioNanotechnology, 303 East Superior, Chicago, IL 60611, USA
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C. Shad Thaxton
3Department of Urology
4Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Northwestern University, Chicago, IL 60611, USA
5Simpson Querrey Institute (SQI) for BioNanotechnology, 303 East Superior, Chicago, IL 60611, USA
6International Institute for Nanotechnology, Evanston, IL 60208, USA
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Marcus E. Peter
1Division of Hematology/Oncology
2Department of Biochemistry and Molecular Genetics
4Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Northwestern University, Chicago, IL 60611, USA
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  • ORCID record for Marcus E. Peter
  • For correspondence: m-peter@northwestern.edu amurmann@northwestern.edu
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Abstract

Trinucleotide repeat (TNR) expansions in the genome cause a number of degenerative diseases. A prominent TNR expansion involves the triplet CAG in the huntingtin (HTT) gene responsible for Huntington’s disease (HD). Pathology is caused by protein and RNA generated from the TNR regions including small siRNA-sized repeat fragments. An inverse correlation between the length of the repeats in HTT and cancer incidence has been reported for HD patients. We now show that siRNAs based on the CAG TNR are toxic to cancer cells by targeting genes that contain long reverse complimentary TNRs in their open reading frames. Of the 60 siRNAs based on the different TNRs, the 6 members in the CAG/CUG family of related TNRs are the most toxic to both human and mouse cancer cells. siCAG/CUG TNR-based siRNAs induce cell death in vitro in all tested cancer cell lines and slow down tumor growth in a preclinical mouse model of ovarian cancer with no signs of toxicity to the mice. We propose to explore TNR-based siRNAs as a novel form of anti-cancer reagents.

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Posted January 12, 2018.
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Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells
Andrea E. Murmann, Quan Q. Gao, William Putzbach, Monal Patel, Elizabeth T. Bartom, Calvin Law, Bryan Bridgeman, Siquan Chen, Kaylin M. McMahon, C. Shad Thaxton, Marcus E. Peter
bioRxiv 247429; doi: https://doi.org/10.1101/247429
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Small interfering RNAs based on huntingtin trinucleotide repeats are highly toxic to cancer cells
Andrea E. Murmann, Quan Q. Gao, William Putzbach, Monal Patel, Elizabeth T. Bartom, Calvin Law, Bryan Bridgeman, Siquan Chen, Kaylin M. McMahon, C. Shad Thaxton, Marcus E. Peter
bioRxiv 247429; doi: https://doi.org/10.1101/247429

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