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Small interfering RNA s based on huntingtin trinucleotide repeats are highly toxic to cancer cells
Author(s) -
Murmann Andrea E,
Gao Quan Q,
Putzbach William E,
Patel Monal,
Bartom Elizabeth T,
Law Calvin Y,
Bridgeman Bryan,
Chen Siquan,
McMahon Kaylin M,
Thaxton C Shad,
Peter Marcus E
Publication year - 2018
Publication title -
embo reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.584
H-Index - 184
eISSN - 1469-3178
pISSN - 1469-221X
DOI - 10.15252/embr.201745336
Subject(s) - huntingtin , trinucleotide repeat expansion , rna , biology , genetics , microbiology and biotechnology , gene , allele , mutant
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 si RNA ‐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 si RNA s based on the CAG TNR are toxic to cancer cells by targeting genes that contain long reverse complementary TNR s in their open reading frames. Of the 60 si RNA s based on the different TNR s, the six members in the CAG / CUG family of related TNR s are the most toxic to both human and mouse cancer cells. si CAG / CUG TNR ‐based si RNA s 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 si RNA s as a novel form of anticancer reagents.