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

Gian P. Sepulveda; Ekaterina S. Gushchanskaia; Alexandra Mora-Martin; Ruben Esse; Iana Nikorich; Ainhoa Ceballos; Julian Kwan; Benjamin C. Blum; Prakruti Dholiya; Andrew Emili; Valentina Perissi; Maria Dafne Cardamone; Alla Grishok

doi:10.1101/2024.02.06.579191

Molecular BiologybioRxivFeb 6, 2024

Preprint

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

Gian P. Sepulveda, Ekaterina S. Gushchanskaia iD, Alexandra Mora-Martin iD, Ruben Esse iD, Iana Nikorich, Ainhoa Ceballos iD, Julian Kwan iD, Benjamin C. Blum iD, Prakruti Dholiya, Andrew Emili iD, Valentina Perissi iD, Maria Dafne Cardamone iD, Alla Grishok iD

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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