Genome-scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer
Functional redundancy shared by paralog genes may afford protection against genetic perturbations, but it can also result in genetic vulnerabilities due to mutual interdependency 1-5 . Here, we surveyed genome-scale short hairpin RNA and CRISPR screening data on hundreds of cancer cell lines and ide...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Science and Business Media LLC
2020
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| Online Access: | https://hdl.handle.net/1721.1/128676 |
| _version_ | 1826207009204076544 |
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| author | Viswanathan, Srinivas R. Nogueira, Marina F. Buss, Colin G. Krill-Burger, John M. Wawer, Mathias J. Malolepsza, Edyta Berger, Ashton C. Choi, Peter S. Shih, Juliann Taylor, Alison M. Tanenbaum, Benjamin Pedamallu, Chandra Sekhar Cherniack, Andrew D. Tamayo, Pablo Strathdee, Craig A. Lage, Kasper Carr, Steven A. Schenone, Monica Bhatia, Sangeeta N. Vazquez, Francisca Tsherniak, Aviad Hahn, William C. Meyerson, Matthew |
| author2 | Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science |
| author_facet | Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Viswanathan, Srinivas R. Nogueira, Marina F. Buss, Colin G. Krill-Burger, John M. Wawer, Mathias J. Malolepsza, Edyta Berger, Ashton C. Choi, Peter S. Shih, Juliann Taylor, Alison M. Tanenbaum, Benjamin Pedamallu, Chandra Sekhar Cherniack, Andrew D. Tamayo, Pablo Strathdee, Craig A. Lage, Kasper Carr, Steven A. Schenone, Monica Bhatia, Sangeeta N. Vazquez, Francisca Tsherniak, Aviad Hahn, William C. Meyerson, Matthew |
| author_sort | Viswanathan, Srinivas R. |
| collection | MIT |
| description | Functional redundancy shared by paralog genes may afford protection against genetic perturbations, but it can also result in genetic vulnerabilities due to mutual interdependency 1-5 . Here, we surveyed genome-scale short hairpin RNA and CRISPR screening data on hundreds of cancer cell lines and identified MAGOH and MAGOHB, core members of the splicing-dependent exon junction complex, as top-ranked paralog dependencies 6-8 . MAGOHB is the top gene dependency in cells with hemizygous MAGOH deletion, a pervasive genetic event that frequently occurs due to chromosome 1p loss. Inhibition of MAGOHB in a MAGOH-deleted context compromises viability by globally perturbing alternative splicing and RNA surveillance. Dependency on IPO13, an importin-β receptor that mediates nuclear import of the MAGOH/B-Y14 heterodimer 9 , is highly correlated with dependency on both MAGOH and MAGOHB. Both MAGOHB and IPO13 represent dependencies in murine xenografts with hemizygous MAGOH deletion. Our results identify MAGOH and MAGOHB as reciprocal paralog dependencies across cancer types and suggest a rationale for targeting the MAGOHB-IPO13 axis in cancers with chromosome 1p deletion. |
| first_indexed | 2024-09-23T13:42:03Z |
| format | Article |
| id | mit-1721.1/128676 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T13:42:03Z |
| publishDate | 2020 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1286762022-09-28T15:40:12Z Genome-scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer Viswanathan, Srinivas R. Nogueira, Marina F. Buss, Colin G. Krill-Burger, John M. Wawer, Mathias J. Malolepsza, Edyta Berger, Ashton C. Choi, Peter S. Shih, Juliann Taylor, Alison M. Tanenbaum, Benjamin Pedamallu, Chandra Sekhar Cherniack, Andrew D. Tamayo, Pablo Strathdee, Craig A. Lage, Kasper Carr, Steven A. Schenone, Monica Bhatia, Sangeeta N. Vazquez, Francisca Tsherniak, Aviad Hahn, William C. Meyerson, Matthew Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science Koch Institute for Integrative Cancer Research at MIT Functional redundancy shared by paralog genes may afford protection against genetic perturbations, but it can also result in genetic vulnerabilities due to mutual interdependency 1-5 . Here, we surveyed genome-scale short hairpin RNA and CRISPR screening data on hundreds of cancer cell lines and identified MAGOH and MAGOHB, core members of the splicing-dependent exon junction complex, as top-ranked paralog dependencies 6-8 . MAGOHB is the top gene dependency in cells with hemizygous MAGOH deletion, a pervasive genetic event that frequently occurs due to chromosome 1p loss. Inhibition of MAGOHB in a MAGOH-deleted context compromises viability by globally perturbing alternative splicing and RNA surveillance. Dependency on IPO13, an importin-β receptor that mediates nuclear import of the MAGOH/B-Y14 heterodimer 9 , is highly correlated with dependency on both MAGOH and MAGOHB. Both MAGOHB and IPO13 represent dependencies in murine xenografts with hemizygous MAGOH deletion. Our results identify MAGOH and MAGOHB as reciprocal paralog dependencies across cancer types and suggest a rationale for targeting the MAGOHB-IPO13 axis in cancers with chromosome 1p deletion. National Cancer Institute (Grant 1R35CA197568) 2020-11-30T15:54:04Z 2020-11-30T15:54:04Z 2018-06 2017-10 2019-05-09T17:18:06Z Article http://purl.org/eprint/type/JournalArticle 1061-4036 1546-1718 https://hdl.handle.net/1721.1/128676 Viswanathan, Srinivas R. et al. "Genome-scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer." Nature Genetics 50, 7 (June 2018): 937–943 © 2018 The Author(s) en http://dx.doi.org/10.1038/s41588-018-0155-3 Nature Genetics Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Springer Science and Business Media LLC PMC |
| spellingShingle | Viswanathan, Srinivas R. Nogueira, Marina F. Buss, Colin G. Krill-Burger, John M. Wawer, Mathias J. Malolepsza, Edyta Berger, Ashton C. Choi, Peter S. Shih, Juliann Taylor, Alison M. Tanenbaum, Benjamin Pedamallu, Chandra Sekhar Cherniack, Andrew D. Tamayo, Pablo Strathdee, Craig A. Lage, Kasper Carr, Steven A. Schenone, Monica Bhatia, Sangeeta N. Vazquez, Francisca Tsherniak, Aviad Hahn, William C. Meyerson, Matthew Genome-scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer |
| title | Genome-scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer |
| title_full | Genome-scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer |
| title_fullStr | Genome-scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer |
| title_full_unstemmed | Genome-scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer |
| title_short | Genome-scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer |
| title_sort | genome scale analysis identifies paralog lethality as a vulnerability of chromosome 1p loss in cancer |
| url | https://hdl.handle.net/1721.1/128676 |
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