A CAF40-binding motif facilitates recruitment of the CCR4-NOT complex to mRNAs targeted by Drosophila Roquin

Human (Hs) Roquin1 and Roquin2 are RNA-binding proteins that promote mRNA target degradation through the recruitment of the CCR4-NOT deadenylase complex and are implicated in the prevention of autoimmunity. Roquin1 recruits CCR4-NOT via a C-terminal region that is not conserved in Roquin2 or in invertebrate Roquin. Here we show that Roquin2 and Drosophila melanogaster (Dm) Roquin also interact with the CCR4-NOT complex through their C-terminal regions. The C-terminal region of Dm Roquin contains multiple motifs that mediate CCR4-NOT binding. One motif binds to the CAF40 subunit of the CCR4-NOT complex. The crystal structure of the Dm Roquin CAF40-binding motif (CBM) bound to CAF40 reveals that the CBM adopts an a-helical conformation upon binding to a conserved surface of CAF40. Thus, despite the lack of sequence conservation, the C-terminal regions of Roquin proteins act as an effector domain that represses the expression of mRNA targets via recruitment of the CCR4-NOT complex

Supplementary Table 1 from N-myc–Mediated Translation Control Is a Therapeutic Vulnerability in Medulloblastoma

&lt;p&gt;RNA abundance of Rapalink-1 and Rapamycin treated samples&lt;/p&gt;</jats:p

Supplementary Table 2 from N-myc–Mediated Translation Control Is a Therapeutic Vulnerability in Medulloblastoma

&lt;p&gt;RPF abundance of Rapalink-1 and Rapamycin treated samples&lt;/p&gt;</jats:p

Supplementary Table 3 from N-myc–Mediated Translation Control Is a Therapeutic Vulnerability in Medulloblastoma

&lt;p&gt;Translation efficiency in Rapalink-1 and Rapamycin treated samples&lt;/p&gt;</jats:p

Supplementary Data from N-myc–Mediated Translation Control Is a Therapeutic Vulnerability in Medulloblastoma

&lt;p&gt;7 Supplementary Figures and Legends&lt;/p&gt;</jats:p

N-myc-Mediated Translation Control Is a Therapeutic Vulnerability in Medulloblastoma.

Deregulation of neuroblastoma-derived myc (N-myc) is a leading cause of malignant brain tumors in children. To target N-myc-driven medulloblastoma, most research has focused on identifying genomic alterations or on the analysis of the medulloblastoma transcriptome. Here, we have broadly characterized the translatome of medulloblastoma and shown that N-myc unexpectedly drives selective translation of transcripts that promote protein homeostasis. Cancer cells are constantly exposed to proteotoxic stress associated with alterations in protein production or folding. It remains poorly understood how cancers cope with proteotoxic stress to promote their growth. Here, our data revealed that N-myc regulates the expression of specific components (∼5%) of the protein folding machinery at the translational level through the major cap binding protein, eukaryotic initiation factor eIF4E. Reducing eIF4E levels in mouse models of medulloblastoma blocked tumorigenesis. Importantly, targeting Hsp70, a protein folding chaperone translationally regulated by N-myc, suppressed tumor growth in mouse and human medulloblastoma xenograft models. These findings reveal a previously hidden molecular program that promotes medulloblastoma formation and identify new therapies that may have impact in the clinic.SignificanceTranslatome analysis in medulloblastoma shows that N-myc drives selective translation of transcripts that promote protein homeostasis and that represent new therapeutic vulnerabilities

Supplementary Table 2 from N-myc–Mediated Translation Control Is a Therapeutic Vulnerability in Medulloblastoma

RPF abundance of Rapalink-1 and Rapamycin treated samples</p

Supplementary Data from N-myc–Mediated Translation Control Is a Therapeutic Vulnerability in Medulloblastoma

7 Supplementary Figures and Legends</p

Supplementary Table 3 from N-myc–Mediated Translation Control Is a Therapeutic Vulnerability in Medulloblastoma

Translation efficiency in Rapalink-1 and Rapamycin treated samples</p

Supplementary Table 1 from N-myc–Mediated Translation Control Is a Therapeutic Vulnerability in Medulloblastoma

RNA abundance of Rapalink-1 and Rapamycin treated samples</p