Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5

Mavrakis, K. J.; McDonald, E. R.; Schlabach, M. R.; Billy, E.; Hoffman, G. R.; deWeck, A.; Ruddy, D. A.; Venkatesan, K.; Yu, J.; McAllister, G.; Stump, M.; deBeaumont, R.; Ho, S.; Yue, Y.; Liu, Y.; Yan-Neale, Y.; Yang, G.; Lin, F.; Yin, H.; Gao, H.; Kipp, D. R.; Zhao, S.; McNamara, J. T.; Sprague, E. R.; Zheng, B.; Lin, Y.; Cho, Y. S.; Gu, J.; Crawford, K.; Ciccone, D.; Vitari, A. C.; Lai, A.; Capka, V.; Hurov, K.; Porter, J. A.; Tallarico, J.; Mickanin, C.; Lees, E.; Pagliarini, R.; Keen, N.; Schmelzle, T.; Hofmann, F.; Stegmeier, F.; Sellers, W. R.

doi:10.1126/science.aad5944

Title: Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5

Journal Article · Thu Feb 11 00:00:00 EST 2016 · Science

DOI:https://doi.org/10.1126/science.aad5944· OSTI ID:1404991

Mavrakis, K. J.; McDonald, E. R.; Schlabach, M. R.; Billy, E.; Hoffman, G. R.; deWeck, A.; Ruddy, D. A.; Venkatesan, K.; Yu, J.; McAllister, G.; Stump, M.; deBeaumont, R.; Ho, S.; Yue, Y.; Liu, Y.; Yan-Neale, Y.; Yang, G.; Lin, F.; Yin, H.; Gao, H. more »

5-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway. The MTAP gene is frequently deleted in human cancers because of its chromosomal proximity to the tumor suppressor gene CDKN2A. By interrogating data from a large-scale short hairpin RNA–mediated screen across 390 cancer cell line models, we found that the viability of MTAP-deficient cancer cells is impaired by depletion of the protein arginine methyltransferase PRMT5. MTAP-deleted cells accumulate the metabolite methylthioadenosine (MTA), which we found to inhibit PRMT5 methyltransferase activity. Deletion of MTAP in MTAP-proficient cells rendered them sensitive to PRMT5 depletion. Conversely, reconstitution of MTAP in an MTAP-deficient cell line rescued PRMT5 dependence. Thus, MTA accumulation in MTAP–deleted cancers creates a hypomorphic PRMT5 state that is selectively sensitized toward further PRMT5 inhibition. Inhibitors of PRMT5 that leverage this dysregulated metabolic state merit further investigation as a potential therapy for MTAP/CDKN2A-deleted tumors.

Cite

Export

Save

Research Organization:: Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: INDUSTRY

OSTI ID:: 1404991

Journal Information:: Science, Vol. 351, Issue 6278; ISSN 0036-8075

Publisher:: AAAS

Country of Publication:: United States

Language:: ENGLISH

References (28)

ATARiS: Computational quantification of gene suppression phenotypes from multisample RNAi screens Shao, D. D.; Tsherniak, A.; Gopal, S. Genome Research, Vol. 23, Issue 4 https://doi.org/10.1101/gr.143586.112	journal	December 2012
DNA sequencing and CRISPR-Cas9 gene editing for target validation in mammalian cells Smurnyy, Yegor; Cai, Mi; Wu, Hua Nature Chemical Biology, Vol. 10, Issue 8 https://doi.org/10.1038/nchembio.1550	journal	June 2014
Direct and tumor microenvironment mediated influences of 5′-deoxy-5′-(methylthio)adenosine on tumor progression of malignant melanoma Stevens, Axel P.; Spangler, Barbara; Wallner, Susanne Journal of Cellular Biochemistry, Vol. 106, Issue 2 https://doi.org/10.1002/jcb.21984	journal	February 2009
Functional epigenetics approach identifies BRM/SMARCA2 as a critical synthetic lethal target in BRG1-deficient cancers Hoffman, G. R.; Rahal, R.; Buxton, F. Proceedings of the National Academy of Sciences, Vol. 111, Issue 8 https://doi.org/10.1073/pnas.1316793111	journal	February 2014
A selective inhibitor of PRMT5 with in vivo and in vitro potency in MCL models Chan-Penebre, Elayne; Kuplast, Kristy G.; Majer, Christina R. Nature Chemical Biology, Vol. 11, Issue 6 https://doi.org/10.1038/nchembio.1810	journal	April 2015
Overview of the CCP 4 suite and current developments Winn, Martyn D.; Ballard, Charles C.; Cowtan, Kevin D. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444910045749	journal	March 2011
Vesicular Stomatitis Viruses Resistant to the Methylase Inhibitor Sinefungin Upregulate RNA Synthesis and Reveal Mutations That Affect mRNA Cap Methylation Li, J.; Chorba, J. S.; Whelan, S. P. J. Journal of Virology, Vol. 81, Issue 8 https://doi.org/10.1128/JVI.02681-06	journal	February 2007
The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity Barretina, Jordi; Caponigro, Giordano; Stransky, Nicolas Nature, Vol. 483, Issue 7391 https://doi.org/10.1038/nature11003	journal	March 2012
Structure of the Arginine Methyltransferase PRMT5-MEP50 Reveals a Mechanism for Substrate Specificity Ho, Meng-Chiao; Wilczek, Carola; Bonanno, Jeffrey B. PLoS ONE, Vol. 8, Issue 2 https://doi.org/10.1371/journal.pone.0057008	journal	February 2013
Features and development of Coot Emsley, P.; Lohkamp, B.; Scott, W. G. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 4 https://doi.org/10.1107/S0907444910007493	journal	March 2010
RioK1, a New Interactor of Protein Arginine Methyltransferase 5 (PRMT5), Competes with pICln for Binding and Modulates PRMT5 Complex Composition and Substrate Specificity Guderian, Gernot; Peter, Christoph; Wiesner, Julia Journal of Biological Chemistry, Vol. 286, Issue 3 https://doi.org/10.1074/jbc.M110.148486	journal	November 2010
PRMT5 (Janus Kinase-binding Protein 1) Catalyzes the Formation of Symmetric Dimethylarginine Residues in Proteins Branscombe, Tina L.; Frankel, Adam; Lee, Jin-Hyung Journal of Biological Chemistry, Vol. 276, Issue 35 https://doi.org/10.1074/jbc.M105412200	journal	June 2001
A Transition State Analogue of 5′-Methylthioadenosine Phosphorylase Induces Apoptosis in Head and Neck Cancers Basu, Indranil; Cordovano, Grace; Das, Ishita Journal of Biological Chemistry, Vol. 282, Issue 29 https://doi.org/10.1074/jbc.M702287200	journal	June 2007
Methylthioadenosine toxicity and metabolism to methionine in mammalian cells Christa, L.; Kersual, J.; Augé, J. Biochemical Journal, Vol. 255, Issue 1 https://doi.org/10.1042/bj2550145	journal	October 1988
An introduction to data reduction: space-group determination, scaling and intensity statistics Evans, Philip R. Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S090744491003982X	journal	March 2011
Deregulation of protein methylation in melanoma Limm, Katharina; Ott, Corinna; Wallner, Susanne European Journal of Cancer, Vol. 49, Issue 6 https://doi.org/10.1016/j.ejca.2012.11.026	journal	April 2013
Enzyme-Dependent Lysine Deprotonation in EZH2 Catalysis Kipp, D. Randal; Quinn, Christopher M.; Fortin, Pascal D. Biochemistry, Vol. 52, Issue 39 https://doi.org/10.1021/bi400805w	journal	September 2013
How good are my data and what is the resolution? Evans, Philip R.; Murshudov, Garib N. Acta Crystallographica Section D Biological Crystallography, Vol. 69, Issue 7 https://doi.org/10.1107/S0907444913000061	journal	June 2013
Methylthioadenosine Phosphorylase Regulates Ornithine Decarboxylase by Production of Downstream Metabolites Subhi, Ahmad L.; Diegelman, Paula; Porter, Carl W. Journal of Biological Chemistry, Vol. 278, Issue 50 https://doi.org/10.1074/jbc.M308451200	journal	September 2003
Salvage of 5′-deoxy-methylthioadenosine into purines and methionine by lymphoid cells and inhibition of cell proliferation Christa, Laurence; Thuillier, Laure; Munier, Annie Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Vol. 803, Issue 1-2 https://doi.org/10.1016/0167-4889(84)90048-X	journal	February 1984
Passenger deletions generate therapeutic vulnerabilities in cancer Muller, Florian L.; Colla, Simona; Aquilanti, Elisa Nature, Vol. 488, Issue 7411 https://doi.org/10.1038/nature11331	journal	August 2012
Data processing and analysis with the autoPROC toolbox Vonrhein, Clemens; Flensburg, Claus; Keller, Peter Acta Crystallographica Section D Biological Crystallography, Vol. 67, Issue 4 https://doi.org/10.1107/S0907444911007773	journal	March 2011
Crystal structure of the human PRMT5:MEP50 complex Antonysamy, S.; Bonday, Z.; Campbell, R. M. Proceedings of the National Academy of Sciences, Vol. 109, Issue 44 https://doi.org/10.1073/pnas.1209814109	journal	October 2012
Tumorigenic activity and therapeutic inhibition of Rheb GTPase Mavrakis, K. J.; Zhu, H.; Silva, R. L. A. Genes & Development, Vol. 22, Issue 16 https://doi.org/10.1101/gad.1690808	journal	August 2008
Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation Qi, W.; Chan, H.; Teng, L. Proceedings of the National Academy of Sciences, Vol. 109, Issue 52 https://doi.org/10.1073/pnas.1210371110	journal	December 2012
Genetic Screens in Human Cells Using the CRISPR-Cas9 System Wang, Tim; Wei, Jenny J.; Sabatini, David M. Science, Vol. 343, Issue 6166 https://doi.org/10.1126/science.1246981	journal	December 2013
Full utilization of a mass spectrometer using on-demand sharing with multiple LC units: On-demand sharing of MS Li, Shu; Hao, Qin; Gounarides, John Journal of Mass Spectrometry, Vol. 47, Issue 8 https://doi.org/10.1002/jms.3061	journal	August 2012
MTAP deletion confers enhanced dependency on the PRMT5 arginine methyltransferase in cancer cells Kryukov, Gregory V.; Wilson, Frederick H.; Ruth, Jason R. Science, Vol. 351, Issue 6278 https://doi.org/10.1126/science.aad5214	journal	February 2016

Similar Records

Discovery of AG-270, a First-in-Class Oral MAT2A Inhibitor for the Treatment of Tumors with Homozygous MTAP Deletion

Journal Article · Thu Apr 08 00:00:00 EDT 2021 · Journal of Medicinal Chemistry · OSTI ID:1404991

Konteatis, Zenon; Travins, Jeremy; Gross, Stefan; +24 more

The use of methylthioadenosine phosphorylase activity to select for human chromosome 9 in interspecies and intraspecies hybrid cells

Journal Article · Wed Sep 01 00:00:00 EDT 1993 · Somatic Cell and Molecular Genetics; (United States) · OSTI ID:1404991

Porterfield, B W; Pomykala, H; Maltepe, E; +3 more

Analysis of tumor suppressor gene on human chromosome 9 in mouse x human somatic cell hybrids

Journal Article · Thu Sep 01 00:00:00 EDT 1994 · Somatic Cell and Molecular Genetics · OSTI ID:1404991

Porterfield, B W; Olopade, O I; Rowley, J D; +1 more

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
60 APPLIED LIFE SCIENCES

Title: Disordered methionine metabolism in MTAP/CDKN2A-deleted cancers leads to dependence on PRMT5

Citation Formats

References (28)

Similar Records

Related Subjects