Proteolytic activation of c-MYC facilitated by DOT1L
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (15)
Gian P. Sepulveda
Department of Biochemistry and Cell Biology, Chobanian and Avedisian School of Medicine, Boston University
Karol Nawalaniec
Department of Biochemistry and Cell Biology, Chobanian and Avedisian School of Medicine, Boston University
Iana Nikorich
Department of Biochemistry and Cell Biology, Chobanian and Avedisian School of Medicine, Boston University
Ekaterina S. Guschanskaia
Department of Biochemistry and Cell Biology, Chobanian and Avedisian School of Medicine, Boston University
Alexandra Mora-Martin
Department of Biochemistry and Cell Biology, Chobanian and Avedisian School of Medicine, Boston University
Ruben Esse
Department of Biochemistry and Cell Biology, Chobanian and Avedisian School of Medicine, Boston University
Ainhoa Ceballos
Department of Biochemistry and Molecular Biophysics, College of Physicians and Surgeons, Columbia University
Chaoshuang Xia
Department of Biochemistry and Cell Biology, Chobanian and Avedisian School of Medicine, Boston University
Julian Kwan
Center for Network Systems Biology, Boston University
Benjamin C. Blum
Center for Network Systems Biology, Boston University
Andrew Emili
Department of Biochemistry and Cell Biology, Chobanian and Avedisian School of Medicine, Boston University
Maria D. Cardamone
Department of Biochemistry and Cell Biology, Chobanian and Avedisian School of Medicine, Boston University
Valentina Perissi
Department of Biochemistry and Cell Biology, Chobanian and Avedisian School of Medicine, Boston University
Catherine E. Costello
Department of Biochemistry and Cell Biology, Chobanian and Avedisian School of Medicine, Boston University
Alla Grishok
Department of Biochemistry and Cell Biology, Chobanian and Avedisian School of Medicine, Boston University