A publication from the Grishok Lab: Proteolytic activation of c-MYC facilitated by DOT1L, appeared in PNAS online on July 28, 2026.
https://www.pnas.org/doi/10.1073/pnas.2525603123
This is the result of many years of work by several generations of lab members, including graduate students Gian Sepulveda and Karol Nawalaniec, postdocs Katia Guschanskaia and Ruben Esse, research fellow Alexandra Mora-Martin, and undergraduate Iana Nikorich, as well as great colleagues from the department, Dafne Cardamone and Valentina Perissi, Chaoshuang Xia and Cathy Costello, and Andrew Emili’s group.
The figure shows a putative interaction between the catalytic aspartic acid of the DOT1L protease and the PLVL cleavage sequence on c-MYC identified by mass spectrometry.
Below is the citation of significance from the manuscript text.
“Significance:
Proteolytic activation of transcription factors has proven to serve biologically important regulatory roles. For example, cleavage of Sterol Regulatory Element-Binding Protein (SREBP) in the cytoplasmic compartments, which releases its DNA-binding domain for translocation to the nucleus, is a fundamental regulatory step in cholesterol metabolism. Here, we present evidence of protease activity of a nuclear methyltransferase enzyme, Dot1-like (DOT1L), and propose that transcription factors can be activated by a proteolytic cleavage after they are transported to the nucleus. Moreover, we show that in the nucleus, the critical oncoprotein cellular myelocytomatosis (c-MYC) is cleaved at a specific position in its sequence. Our findings open new directions for transcription regulation research and thus may lead to the development of clinically relevant modulators of c-MYC and other transcription factors.”