Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma

Damon A Hofman; Jorge Ruiz-Orera; Ian Yannuzzi; Rakesh Murugesan; Adam Brown; Karl R Clauser; Alexandra L Condurat; Jip T van Dinter; Sem A G Engels; Amy Goodale; Jasper van der Lugt; Tanaz Abid; Li Wang; Kevin N Zhou; Jayne Vogelzang; Keith L Ligon; Timothy N Phoenix; Jennifer A Roth; David E Root; Norbert Hubner; Todd R Golub; Pratiti Bandopadhayay; Sebastiaan van Heesch; John R Prensner

doi:10.1101/2023.05.04.539399

Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma

Damon A Hofman, Jorge Ruiz-Orera, Ian Yannuzzi, Rakesh Murugesan, Adam Brown, Karl R Clauser, Alexandra L Condurat, Jip T van Dinter, Sem A G Engels, Amy Goodale, Jasper van der Lugt, Tanaz Abid, Li Wang, Kevin N Zhou, Jayne Vogelzang, Keith L Ligon, Timothy N Phoenix, Jennifer A Roth, David E Root, Norbert HubnerTodd R Golub, Pratiti Bandopadhayay, Sebastiaan van Heesch, John R Prensner

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A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation. Currently, it is unknown whether medulloblastoma dysregulates the translation of putatively oncogenic non-canonical open reading frames. To address this question, we performed ribosome profiling of 32 medulloblastoma tissues and cell lines and observed widespread non-canonical ORF translation. We then developed a step-wise approach to employ multiple CRISPR-Cas9 screens to elucidate functional non-canonical ORFs implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream open reading frames (uORFs) exhibited selective functionality independent of the main coding sequence. One of these, ASNSD1-uORF or ASDURF, was upregulated, associated with the MYC family oncogenes, and was required for medulloblastoma cell survival through engagement with the prefoldin-like chaperone complex. Our findings underscore the fundamental importance of non-canonical ORF translation in medulloblastoma and provide a rationale to include these ORFs in future cancer genomics studies seeking to define new cancer targets.

Originele taal-2	Engels
Tijdschrift	bioRxiv
DOI's	https://doi.org/10.1101/2023.05.04.539399
Status	Gepubliceerd - 6 mei 2023

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Hofman, D. A., Ruiz-Orera, J., Yannuzzi, I., Murugesan, R., Brown, A., Clauser, K. R., Condurat, A. L., van Dinter, J. T., Engels, S. A. G., Goodale, A., van der Lugt, J., Abid, T., Wang, L., Zhou, K. N., Vogelzang, J., Ligon, K. L., Phoenix, T. N., Roth, J. A., Root, D. E., ... Prensner, J. R. (2023). Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma. bioRxiv. https://doi.org/10.1101/2023.05.04.539399

@article{e918dd94c5434c25882d7b2e991280ae,

title = "Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma",

abstract = "A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation. Currently, it is unknown whether medulloblastoma dysregulates the translation of putatively oncogenic non-canonical open reading frames. To address this question, we performed ribosome profiling of 32 medulloblastoma tissues and cell lines and observed widespread non-canonical ORF translation. We then developed a step-wise approach to employ multiple CRISPR-Cas9 screens to elucidate functional non-canonical ORFs implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream open reading frames (uORFs) exhibited selective functionality independent of the main coding sequence. One of these, ASNSD1-uORF or ASDURF, was upregulated, associated with the MYC family oncogenes, and was required for medulloblastoma cell survival through engagement with the prefoldin-like chaperone complex. Our findings underscore the fundamental importance of non-canonical ORF translation in medulloblastoma and provide a rationale to include these ORFs in future cancer genomics studies seeking to define new cancer targets.",

author = "Hofman, {Damon A} and Jorge Ruiz-Orera and Ian Yannuzzi and Rakesh Murugesan and Adam Brown and Clauser, {Karl R} and Condurat, {Alexandra L} and {van Dinter}, {Jip T} and Engels, {Sem A G} and Amy Goodale and {van der Lugt}, Jasper and Tanaz Abid and Li Wang and Zhou, {Kevin N} and Jayne Vogelzang and Ligon, {Keith L} and Phoenix, {Timothy N} and Roth, {Jennifer A} and Root, {David E} and Norbert Hubner and Golub, {Todd R} and Pratiti Bandopadhayay and {van Heesch}, Sebastiaan and Prensner, {John R}",

year = "2023",

month = may,

day = "6",

doi = "10.1101/2023.05.04.539399",

language = "English",

journal = "bioRxiv",

publisher = "Cold Spring Harbor Laboratory",

}

Hofman, DA, Ruiz-Orera, J, Yannuzzi, I, Murugesan, R, Brown, A, Clauser, KR, Condurat, AL, van Dinter, JT, Engels, SAG, Goodale, A, van der Lugt, J, Abid, T, Wang, L, Zhou, KN, Vogelzang, J, Ligon, KL, Phoenix, TN, Roth, JA, Root, DE, Hubner, N, Golub, TR, Bandopadhayay, P, van Heesch, S & Prensner, JR 2023, 'Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma', bioRxiv. https://doi.org/10.1101/2023.05.04.539399

TY - JOUR

T1 - Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma

AU - Hofman, Damon A

AU - Ruiz-Orera, Jorge

AU - Yannuzzi, Ian

AU - Murugesan, Rakesh

AU - Brown, Adam

AU - Clauser, Karl R

AU - Condurat, Alexandra L

AU - van Dinter, Jip T

AU - Engels, Sem A G

AU - Goodale, Amy

AU - van der Lugt, Jasper

AU - Abid, Tanaz

AU - Wang, Li

AU - Zhou, Kevin N

AU - Vogelzang, Jayne

AU - Ligon, Keith L

AU - Phoenix, Timothy N

AU - Roth, Jennifer A

AU - Root, David E

AU - Hubner, Norbert

AU - Golub, Todd R

AU - Bandopadhayay, Pratiti

AU - van Heesch, Sebastiaan

AU - Prensner, John R

PY - 2023/5/6

Y1 - 2023/5/6

N2 - A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation. Currently, it is unknown whether medulloblastoma dysregulates the translation of putatively oncogenic non-canonical open reading frames. To address this question, we performed ribosome profiling of 32 medulloblastoma tissues and cell lines and observed widespread non-canonical ORF translation. We then developed a step-wise approach to employ multiple CRISPR-Cas9 screens to elucidate functional non-canonical ORFs implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream open reading frames (uORFs) exhibited selective functionality independent of the main coding sequence. One of these, ASNSD1-uORF or ASDURF, was upregulated, associated with the MYC family oncogenes, and was required for medulloblastoma cell survival through engagement with the prefoldin-like chaperone complex. Our findings underscore the fundamental importance of non-canonical ORF translation in medulloblastoma and provide a rationale to include these ORFs in future cancer genomics studies seeking to define new cancer targets.

AB - A hallmark of high-risk childhood medulloblastoma is the dysregulation of RNA translation. Currently, it is unknown whether medulloblastoma dysregulates the translation of putatively oncogenic non-canonical open reading frames. To address this question, we performed ribosome profiling of 32 medulloblastoma tissues and cell lines and observed widespread non-canonical ORF translation. We then developed a step-wise approach to employ multiple CRISPR-Cas9 screens to elucidate functional non-canonical ORFs implicated in medulloblastoma cell survival. We determined that multiple lncRNA-ORFs and upstream open reading frames (uORFs) exhibited selective functionality independent of the main coding sequence. One of these, ASNSD1-uORF or ASDURF, was upregulated, associated with the MYC family oncogenes, and was required for medulloblastoma cell survival through engagement with the prefoldin-like chaperone complex. Our findings underscore the fundamental importance of non-canonical ORF translation in medulloblastoma and provide a rationale to include these ORFs in future cancer genomics studies seeking to define new cancer targets.

U2 - 10.1101/2023.05.04.539399

DO - 10.1101/2023.05.04.539399

M3 - Article

C2 - 37205492

JO - bioRxiv

JF - bioRxiv

ER -

Translation of non-canonical open reading frames as a cancer cell survival mechanism in childhood medulloblastoma

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