Proteolytic activation of c-MYC facilitated by DOT1L.

Authors

Gian P Sepulveda, Karol Nawalaniec, Iana Nikorich, Ekaterina S Guschanskaia, Alexandra Mora-Martin, Ruben Esse, Ainhoa Ceballos, Chaoshuang Xia, Julian Kwan, Benjamin C Blum, Andrew Emili, Maria D Cardamone, Valentina Perissi, Catherine E Costello, Alla Grishok

Published in

Proceedings of the National Academy of Sciences of the United States of America. Volume 123. Issue 31. Pages e2525603123. Aug 04, 2026. Epub Jul 28, 2026.

Abstract

c-MYC is a key regulator of growth and metabolism. Functional and molecular cooperation between the H3K79 methyltransferase DOT1L and c-MYC has been reported in several human cancer types, but the nature of their interaction remains undefined. We demonstrate that DOT1L and MYC [Myc and Mondo-like (MML-1) in Caenorhabditis elegans] coregulate genes in the nematode model and mammalian cancer cells. Moreover, both c-MYC and MML-1 exhibit cleavage products facilitated by DOT1L function. Surprisingly, we found a similarity between a conserved sequence in DOT1 proteins and the DDI-family protease catalytic motif. We characterize a c-MYC sequence preceding the DNA-binding domain as a site of nuclear proteolytic cleavage, demonstrate its importance for transcription activation by c-MYC, and propose that c-MYC is activated by a protease, as previously reported for Nuclear factor erythroid 2-related factor (NRF) and SREBP transcription factors. Our results suggest that DOT1L may activate c-MYC and other transcription factors in the nucleus by acting as a protease.

PMID:
42520114
Bibliographic data and abstract were imported from PubMed on 29 Jul 2026.

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