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The CMG helicase and cancer: a tumor “engine” and weakness with missing mutations

Oncogene volume 42, pages 473–490 (2023)Cite this article

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Abstract

The replicative Cdc45-MCM-GINS (CMG) helicase is a large protein complex that functions in the DNA melting and unwinding steps as a component of replisomes during DNA replication in mammalian cells. Although the CMG performs this important role in cell growth, the CMG is not a simple bystander in cell cycle events. Components of the CMG, specifically the MCM precursors, are also involved in maintaining genomic stability by regulating DNA replication fork speeds, facilitating recovery from replicative stresses, and preventing consequential DNA damage. Given these important functions, MCM/CMG complexes are highly regulated by growth factors such as TGF-ß1 and by signaling factors such as Myc, Cyclin E, and the retinoblastoma protein. Mismanagement of MCM/CMG complexes when these signaling mediators are deregulated, and in the absence of the tumor suppressor protein p53, leads to increased genomic instability and is a contributor to tumorigenic transformation and tumor heterogeneity. The goal of this review is to provide insight into the mechanisms and dynamics by which the CMG is regulated during its assembly and activation in mammalian genomes, and how errors in CMG regulation due to oncogenic changes promote tumorigenesis. Finally, and most importantly, we highlight the emerging understanding of the CMG helicase as an exploitable vulnerability and novel target for therapeutic intervention in cancer.

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Fig. 1: Structure and assembly of the replicative human CMG helicase.
Fig. 2: Mammalian cells load excessive MCM hexamers onto DNA for multiple purposes.
Fig. 3: Transforming growth factor-ß1 cell cycle arrest signaling pathways target multiple aspects of MCM assembly and CMG activation.
Fig. 4: Oncogenes such as Myc and Cyclin E mismanage the reserve MCM/CMGs.
Fig. 5: Human cancers do not contain known cancer-driver mutations in CMG components.
Fig. 6: Rationale for targeting MCMs/CMGs with anti-cancer drugs.

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Funding

This work was supported by the National Pediatric Cancer Foundation (nationalpcf.org; DRR) and research support to MGA from the National Institutes of Health (R01 GM140140-01) and the Adolescent and Young Adult Program at the Moffitt Cancer Center and Research Institute.

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Authors and Affiliations

  1. Cancer Biology and Evolution Program, Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA

    Shengyan Xiang, Damon R. Reed & Mark G. Alexandrow

  2. Molecular Oncology Department, Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA

    Shengyan Xiang & Mark G. Alexandrow

  3. Department of Individualized Cancer Management, Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA

    Damon R. Reed

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Composed and edited manuscript: SX. Designed figures, composed, and edited manuscript: DRR and MGA.

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Xiang, S., Reed, D.R. & Alexandrow, M.G. The CMG helicase and cancer: a tumor “engine” and weakness with missing mutations. Oncogene 42, 473–490 (2023). https://doi.org/10.1038/s41388-022-02572-8

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