Omomyc Reveals New Mechanisms To Inhibit the MYC Oncogene

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2019 Sep 11

PMID 31501275

Citations 43

Authors

Mark J Demma

Claudio Mapelli

Angie Sun

Smaranda Bodea

Benjamin Ruprecht

Sarah Javaid

Derek Wiswell

Eric Muise

Shiying Chen

John Zelina

Federica Orvieto

Alessia Santoprete

Simona Altezza

Federica Tucci

Enrique Escandon

Brian Hall

Kallol Ray

Abbas Walji

Jennifer ONeil

Affiliations

Soon will be listed here.

Abstract

The MYC oncogene is upregulated in human cancers by translocation, amplification, and mutation of cellular pathways that regulate Myc. Myc/Max heterodimers bind to E box sequences in the promoter regions of genes and activate transcription. The MYC inhibitor Omomyc can reduce the ability of MYC to bind specific box sequences in promoters of MYC target genes by binding directly to E box sequences as demonstrated by romatin mmunorecipitation (CHIP). Here, we demonstrate by both a roximity igation ssay (PLA) and double chromatin immunoprecipitation (ReCHIP) that Omomyc preferentially binds to Max, not Myc, to mediate inhibition of MYC-mediated transcription by replacing MYC/MAX heterodimers with Omomyc/MAX heterodimers. The formation of Myc/Max and Omomyc/Max heterodimers occurs cotranslationally; Myc, Max, and Omomyc can interact with ribosomes and Max RNA under conditions in which ribosomes are intact. Taken together, our data suggest that the mechanism of action of Omomyc is to bind DNA as either a homodimer or a heterodimer with Max that is formed cotranslationally, revealing a novel mechanism to inhibit the MYC oncogene. We find that , Omomyc distributes quickly to kidneys and liver and has a short effective half-life in plasma, which could limit its use .

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