Project description:Analysis of RISC bound short (s)RNAs in cells infected with HIV-1 reveals a contribution of 6mer seed toxicity to HIV-1 induced cytopathicity
Project description:Analysis of RISC bound short (s)RNAs in cells infected with HIV-1 reveals a contribution of 6mer seed toxicity to HIV-1 induced cytopathicity
Project description:Analysis of RISC bound short (s)RNAs in cells infected with HIV-1 reveals a contribution of 6mer seed toxicity to HIV-1 induced cytopathicity
Project description:Analysis of RISC bound short (s)RNAs in cells infected with HIV-1 reveals a contribution of 6mer seed toxicity to HIV-1 induced cytopathicity
Project description:Analysis of RISC bound short (s)RNAs in cells infected with HIV-1 reveals a contribution of 6mer seed toxicity to HIV-1 induced cytopathicity
Project description:MicroRNAs (miRNAs) are short double-stranded noncoding RNAs (19-23 nucleotides) that regulate gene expression by suppressing mRNAs through RNA interference. Targeting is determined by the seed sequence (position 2-7/8) of the mature miRNA. A minimal G-rich seed of just six nucleotides is highly toxic to cells by targeting genes essential for cell survival. A screen of 215 miRNAs encoded by 17 human pathogenic viruses (v-miRNAs) now suggests that a number of v-miRNAs can kill cells through a G-rich 6mer sequence embedded in their seed. Specifically, we demonstrate that miR-K12-6-5p, an oncoviral mimic of the tumor suppressive miR-15/16 family encoded by human Kaposi sarcoma-associated herpes virus, harbors a noncanonical toxic 6mer seed (position 3-8) and that v-miRNAs are more likely than cellular miRNAs to utilize a noncanonical 6mer seed. Our data suggest that during evolution viruses evolved to use 6mer seed toxicity to kill cells.
Project description:Many small-interfering (si)RNAs are toxic to cancer cells through a 6mer seed sequence (positions 2-7 of the guide strand). Here we performed an siRNA screen with all 4096 6mer seeds revealing a preference for guanine in positions 1 and 2 and a high overall G or C content in the seed of the most toxic siRNAs for four tested human and mouse cell lines. Toxicity of these siRNAs stems from targeting survival genes with C-rich 3'UTRs. The master tumor suppressor miRNA miR-34a-5p is toxic through such a G-rich 6mer seed and is upregulated in cells subjected to genotoxic stress. An analysis of all mature miRNAs suggests that during evolution most miRNAs evolved to avoid guanine at the 5' end of the 6mer seed sequence of the guide strand. In contrast, for certain tumor-suppressive miRNAs the guide strand contains a G-rich toxic 6mer seed, presumably to eliminate cancer cells.
