MYC-induced oncogenesis is dependent on acidic patches within its N-terminal intrinsically disordered domain.

Llombart, V.; O'Connor, D.; Demeulemeester, J.; Bhamra, A.; Surinova, S.; Turna, A.; Fung, K.; Wang, L.; Li, Y.; Rapoz-D'Silva, T.; Ahmed, F.; Niskanen, H.; Stöppelkamp, I.; Hnisz, D.; Bottaro, S.; Fisicaro, C.; He, S.; Look, A. T.; Mansour, M. R.

doi:10.1101/2025.06.16.659507

bioRxiv · 10.1101/2025.06.16.659507

MYC-induced oncogenesis is dependent on acidic patches within its N-terminal intrinsically disordered domain.

Llombart, V.·O'Connor, D.·Demeulemeester, J.·Bhamra, A.·Surinova, S.·Turna, A.·Fung, K.·Wang, L.·Li, Y.·Rapoz-D'Silva, T.·Ahmed, F.·Niskanen, H.·Stöppelkamp, I.·Hnisz, D.·Bottaro, S.·Fisicaro, C.·He, S.·Look, A. T.·Mansour, M. R.

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Abstract

MYC is one of the most enticing therapeutic targets for cancer but clinical-grade inhibitors are still lacking. By site-saturation mutagenesis screening, we identified several evolutionarily conserved acidic patches within the intrinsically-disordered MYC N-terminus that were confirmed to be functionally essential in different cell models and in vivo. Beyond modulating MYCs global transcriptional activity, these negatively charged patches regulate the interaction with chromatin-modifying complexes including those with histone acetyl-transferase activity. One of the key interactions is established with the co-factor TRRAP, a subunit shared between several Histone Acetyl-Transferase complexes. The protein-protein binding between MYC and TRRAP predominantly relies on two of the N-terminal negative clusters that are located outside MYC-Box-II (MBII) and drive oncogenesis. Our work identifies a new multivalent MYC subdomain that presents new therapeutic vulnerabilities providing invaluable insights for the development of new therapeutic approaches.

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Llombart, V., O'Connor, D., Demeulemeester, J., Bhamra, A., Surinova, S., Turna, A., Fung, K., Wang, L., Li, Y., Rapoz-D'Silva, T., Ahmed, F., Niskanen, H., Stöppelkamp, I., Hnisz, D., Bottaro, S., Fisicaro, C., He, S., Look, A. T., Mansour, M. R.. 2025-06-19. MYC-induced oncogenesis is dependent on acidic patches within its N-terminal intrinsically disordered domain.. https://doi.org/10.1101/2025.06.16.659507

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