Myc-driven chromatin accessibility regulates Cdc45 assembly into CMG helicases
Open accessAbstract
Myc-driven tumorigenesis involves a non-transcriptional role for Myc in over-activating replication origins. We show here that the mechanism underlying this process involves a direct role for Myc in activation of Cdc45-MCM-GINS (CMG) helicases at Myc-targeted sites. Myc induces decondensation of higher-order chromatin at targeted sites and is required for chromatin access at a chromosomal origin. Myc-driven chromatin accessibility promotes Cdc45/GINS recruitment to resident MCMs, and activation of CMGs. Myc-Box II, which is necessary for Myc-driven transformation, is required for Myc-induced chromatin accessibility, Cdc45/GINS recruitment, and replication stimulation. Myc interactors GCN5, Tip60, and TRRAP are essential for chromatin unfolding and recruitment of Cdc45, and co-expression of GCN5 or Tip60 with MBII-deficient Myc rescues these events and promotes CMG activation. Finally, Myc and Cdc45 interact and physiologic conditions for CMG assembly require the functions of Myc, MBII, and GCN5 for Cdc45 recruitment and initiation of DNA replication.
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Despite the disordered nature of the Myc TAD, evidence suggests that MB-II becomes a well-defined structure when it interacts with TRRAP, providing an opportunity to develop inhibitors that can block Myc-TRRAP interactions and specifically target Myc-driven cancers.
“Despite the disordered nature of the Myc TAD, evidence suggests that MB-II becomes a well-defined structure when it interacts with TRRAP, providing an opportunity to develop inhibitors that can block Myc-TRRAP interactions and specifically target Myc-driven cancers.432–434”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [433]
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Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
- Authors
- Nepon-Sixt, B. S., Bryant, V. L., & Alexandrow, M. G.
- Affiliations
- Moffitt Cancer Center (US)
- University of South Florida (US)
- Corresponding author
- Alexandrow, Mark G.
- Venue
- Communications Biology
- Published
- 2019-03-22
- Volume
- 2
- Issue
- 1
- Pages
- 110-110
- ISSN
- 2399-3642 (ISSN-L)
- PMC
- PMC6430796
- OpenAlex
- W2922924080
- Cited by
- 25
- References
- 52
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 5 · 2023: 4 · 2022: 6 · 2021: 1 · 2020: 5 · 2019: 1
- FWCI
- 1.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Communications Biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (R01-CA130865, R21-CA155393)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- c-Myc, Cdc45, CMG helicase, chromatin accessibility, DNA replication initiation, MCM helicase, GINS complex, GCN5, Tip60, TRRAP, chromatin decondensation, carcinogenesis, origin of replication
- MeSH terms
- p300-CBP-Associated Factor, Animals, Chromatin, Cricetulus, DNA Replication, DNA Helicases, Enzyme Activation, Humans, Protein Binding, Biomarkers, Genes, myc, CHO Cells, Cell Cycle Proteins, Chromatin Assembly and Disassembly, p300-CBP Transcription Factors
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