E2A SUMOylation promotes HAdV mediated inhibition of the tumor suppressor p53 during infection

Stubbe, M.; Stubbe, H. C.; Mai, J.; Plank, V.; Hofmann, S.; Goettig, L.; Guenther, T.; Grundhoff, A.; Krebs, S.; Groitl, P.; Mayerle, J.; Hay, R. T.; Dobner, T.; Schreiner, S.

doi:10.1101/2025.02.07.636424

bioRxiv · 10.1101/2025.02.07.636424

E2A SUMOylation promotes HAdV mediated inhibition of the tumor suppressor p53 during infection

Stubbe, M.·Stubbe, H. C.·Mai, J.·Plank, V.·Hofmann, S.·Goettig, L.·Guenther, T.·Grundhoff, A.·Krebs, S.·Groitl, P.·Mayerle, J.·Hay, R. T.·Dobner, T.·Schreiner, S.

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Abstract

HAdV express early viral genes to modulate the activity of the cellular tumor suppressor p53 and ensure efficient viral replication, through various processes, whilst some of them are not completely understood. HAdV oncoprotein E1B-55K interactions with SUMO, PML-IV/V and Sp100A are tightly connected to the transforming potential of the viral factor in non-lytic infections. SUMO modified HAdV DNA binding protein (DBP) E2A interacts with PML and Sp100A acting as a molecular bridge between viral replication centers (RCs) and PML tracks. Here, we provide a novel concept showing that HAdV E2A is involved in the inhibition of p53 activity and apoptosis; thus we identified a novel route of exhibiting virus induced oncogenic potential. We revealed an E1B-55K independent localization of p53 within HAdV replication centers marked by E2A. In the absence of any functional E1B-55K protein expression, p53 interacts with E2A. E2A SUMOylation promotes HAdV- mediated inhibition of p53/DNA binding and p53-dependent transactivation by supporting p53 degradation, E1B-55K interaction and colocalization with PML-V that leads to E1B-55K induced upregulation of p53 SUMOylation. In sum, we provide evidence for a novel mechanism by which the HAdV DBP E2A protein inhibits p53- mediated transcriptional activation and apoptotic host cell response. Intriguingly, these findings change the longstanding dogma of host DNA damage response (DDR) inactivation by HAdV infection and offer crucial insights to improve future p53 selective oncolytic virus therapies and adenoviral vectors.

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Stubbe, M., Stubbe, H. C., Mai, J., Plank, V., Hofmann, S., Goettig, L., Guenther, T., Grundhoff, A., Krebs, S., Groitl, P., Mayerle, J., Hay, R. T., Dobner, T., Schreiner, S.. 2025-02-08. E2A SUMOylation promotes HAdV mediated inhibition of the tumor suppressor p53 during infection. https://doi.org/10.1101/2025.02.07.636424

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