DOT1L stimulates MYC/Mondo transcription factor activity by promoting its degradation cycle on chromatin

Sepulveda, G. P.; Gushchanskaia, E. S.; Mora-Martin, A.; Esse, R.; Nikorich, I.; Ceballos, A.; Kwan, J.; Blum, B. C.; Dholiya, P.; Emili, A.; Perissi, V.; Cardamone, M. D.; Grishok, A.

doi:10.1101/2024.02.06.579191

bioRxiv · 10.1101/2024.02.06.579191

DOT1L stimulates MYC/Mondo transcription factor activity by promoting its degradation cycle on chromatin

Sepulveda, G. P.·Gushchanskaia, E. S.·Mora-Martin, A.·Esse, R.·Nikorich, I.·Ceballos, A.·Kwan, J.·Blum, B. C.·Dholiya, P.·Emili, A.·Perissi, V.·Cardamone, M. D.·Grishok, A.

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Abstract

The proto-oncogene c-MYC is a key representative of the MYC transcription factor network regulating growth and metabolism. MML-1 (Myc- and Mondo-like) is its homolog in C. elegans. The functional and molecular cooperation between c-MYC and H3 lysine 79 methyltransferase DOT1L was demonstrated in several human cancer types, and we have earlier discovered the connection between C. elegans MML-1 and DOT-1.1. Here, we demonstrate the critical role of DOT1L/DOT-1.1 in regulating c-MYC/MML-1 target genes genome-wide by ensuring the removal of "spent" transcription factors from chromatin by the nuclear proteasome. Moreover, we uncover a previously unrecognized proteolytic activity of DOT1L, which may facilitate c-MYC turnover. This new mechanism of c-MYC regulation by DOT1L may lead to the development of new approaches for cancer treatment.

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Sepulveda, G. P., Gushchanskaia, E. S., Mora-Martin, A., Esse, R., Nikorich, I., Ceballos, A., Kwan, J., Blum, B. C., Dholiya, P., Emili, A., Perissi, V., Cardamone, M. D., Grishok, A.. 2024-02-07. DOT1L stimulates MYC/Mondo transcription factor activity by promoting its degradation cycle on chromatin. https://doi.org/10.1101/2024.02.06.579191

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