Abstract
The c-Myc oncoprotein promotes cell growth by enhancing ribosomal biogenesis. Overexpression of c-Myc and aberrant ribosomal biogenesis lead to deregulated cell growth and tumorigenesis. Hence, c-Myc activity and ribosomal biogenesis must be tightly coordinated during normal homeostasis. We previously found that ribosomal protein L11 inhibits c-Myc activity by blocking the recruitment of its co-activator transformation/transcription domain-associated protein (TRRAP) to the promoter regions of c-Myc target genes that are transcribed by RNA polymerases I and II. In this study, we extended the role of L11 to the regulation of c-Myc-driven transcription of the 5 S rRNA and tRNA genes by RNA polymerase III. L11 co-resided with c-Myc at the 5 S rRNA and tRNA genes and significantly inhibited the binding of TRRAP to these genes. Knocking down endogenous L11 enhanced c-Myc-dependent transcription of these genes. Interestingly, in response to ribosomal stress induced by the treatment of cells with a low dose of actinomycin D or serum starvation, L11 binding to these genes was increased, and inversely TRRAP binding to these genes was decreased. Consistently, knockdown of L11 rescued the reduction of the expression of these genes by the two treatments. These results demonstrate that L11 suppresses c-Myc-dependent and RNA polymerase III-catalyzed transcription of 5 S rRNA and tRNA genes in response to ribosomal stress, ensuring a tight coordination between c-Myc activity and ribosomal biogenesis.
Highlights
Because we recently showed that L11 inhibits c-Myc-dependent transcription of pre-rRNA, nucleolin, E2F2, and eIF4E genes, which are transcribed by RNA Pol I and II, respectively [18], we wanted to determine whether L11 plays a ubiquitous role in regulating c-Myc-mediated transcription of all three classes of genes by further testing if it affects c-Myc-dependent transcription of the 5 S rRNA and tRNA genes by RNA Pol III
Knockdown of endogenous L11 enhanced the expression of the 5 S rRNA, tRNATyr, and tRNALeu genes by 2-fold. This enhancement was c-Myc-dependent because further ablation of endogenous c-Myc by siRNA drastically reduced the L11 siRNA-induced expression of the above genes. These results suggest that L11 inhibits c-Myc-induced transcription of the 5 S rRNA and tRNA genes in cells
transcription domain-associated protein (TRRAP) binding to these genes was dramatically decreased (Fig. 6B), suggesting that the reduction of TRRAP recruitment to above RNA Pol III-catalyzed genes was not merely due to the reduction of c-Myc binding in the serum-starved cells. These results indicate that L11 competes with TRRAP for binding to the 5 S rRNA and tRNA genes in response to ribosomal stress, further supporting the role of L11 in inhibition of c-Myc-driven transactivational activity toward the RNA Pol III-catalyzed transcription of the 5 S rRNA and tRNA genes by RNA Pol III
Summary
These results suggest that L11 inhibition of c-Myc-driven transcription of the 5 S rRNA, and tRNATyr genes was all significantly reduced in response to Act D treatment for 12 h or serum starvation for 24 h.
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