2. Academic Validation
  3. MYC assembles and stimulates topoisomerases 1 and 2 in a "topoisome"

MYC assembles and stimulates topoisomerases 1 and 2 in a "topoisome"

  • Mol Cell. 2022 Jan 6;82(1):140-158.e12. doi: 10.1016/j.molcel.2021.11.016.
Subhendu K Das 1,  Vladislav Kuzin 2,  Donald P Cameron 2,  Suzanne Sanford 1,  Rajiv Kumar Jha 1,  Zuqin Nie 1,  Marta Trullols Rosello 2,  Ronald Holewinski 3,  Thorkell Andresson 3,  Jan Wisniewski 4,  Toyoaki Natsume 5,  David H Price 6,  Brian A Lewis 1,  Fedor Kouzine 1,  David Levens 7,  Laura Baranello 8
Affiliations

Affiliations

  • 1 Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20814, USA.
  • 2 Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
  • 3 Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Bethesda, MD 21701, USA.
  • 4 Confocal Microscopy and Digital Imaging Facility, National Cancer Institute, Bethesda, MD 20892, USA.
  • 5 Department of Chromosome Science, National Institute of Genetics, Shizuoka 411-8540, Japan; Research Center for Genome & Medical Sciences, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan.
  • 6 Department of Biochemistry, University of Iowa, Iowa City, IA 52242, USA.
  • 7 Laboratory of Pathology, National Cancer Institute, Bethesda, MD 20814, USA. Electronic address: [email protected].
  • 8 Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address: [email protected].
PMID: 34890565 DOI: 10.1016/j.molcel.2021.11.016
Abstract

High-intensity transcription and replication supercoil DNA to levels that can impede or halt these processes. As a potent transcription amplifier and replication accelerator, the proto-oncogene MYC must manage this interfering torsional stress. By comparing gene expression with the recruitment of topoisomerases and MYC to promoters, we surmised a direct association of MYC with Topoisomerase 1 (TOP1) and TOP2 that was confirmed in vitro and in cells. Beyond recruiting topoisomerases, MYC directly stimulates their activities. We identify a MYC-nucleated "topoisome" complex that unites TOP1 and TOP2 and increases their levels and activities at promoters, gene bodies, and enhancers. Whether TOP2A or TOP2B is included in the topoisome is dictated by the presence of MYC versus MYCN, respectively. Thus, in vitro and in cells, MYC assembles tools that simplify DNA topology and promote genome function under high output conditions.

Keywords

DNA topology; Myc; TOP1; TOP2; Topoisomerase; Transcription; cancer; chromatin; polymerase; supercoiling.

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