Myc and the Replicative CMG Helicase: The Creation and Destruction of Cancer

Abstract

Myc‐driven tumorigenesis involves a non‐transcriptional role for Myc in over‐activating replicative Cdc45‐MCM‐GINS (CMG) helicases. Excessive stimulation of CMG helicases by Myc mismanages CMG function by diminishing the number of reserve CMGs necessary for fidelity of DNA replication and recovery from replicative stresses. One potential outcome of these events is the creation of DNA damage that alters genomic structure/function, thereby acting as a driver for tumorigenesis and tumor heterogeneity. Intriguingly, another potential outcome of this Myc‐induced CMG helicase over‐activation is the creation of a vulnerability in cancer whereby tumor cells specifically lack enough unused reserve CMG helicases to recover from fork‐stalling drugs commonly used in chemotherapy. This review provides molecular and clinical support for this provocative hypothesis that excessive activation of CMG helicases by Myc may not only drive tumorigenesis, but also confer an exploitable “reserve CMG helicase vulnerability” that supports developing innovative CMG‐focused therapeutic approaches for cancer management.

Identification of Selective ATP-Competitive CMG Helicase Inhibitors for Cancer Intervention that Disrupt CMG-Replisome Function

“…However, aminocoumarins such as these CMGi may offer clinical advantages with novel modes of action in suppressing tumor growth due to targeted inhibition of the CMG and replisomes. More importantly, oncogenic changes mismanage the regulation of reserve MCMs/CMGs, predicting deficiencies in CMG functionality and a tumor-specific vulnerability in the CMG relative to non-tumor cells 1 , 46 . In support of this, our results show that tumor cells are indeed selectively sensitive to CMGi, and, importantly, that a therapeutic window exists for targeting the CMG helicase with CMGi.…”

DNA replication: Mechanisms and therapeutic interventions for diseases

“…369 Myc is one crucial factor in regulating cell growth and tumorigenesis, overexpression of Myc enhances the Cdc45 DNA binding ability and replication fork stalling, which indicates Myc-induced RS collaborates with Cdc45 in tumor development. 370,371 In summary, excessive expression of CMG is generally related with tumor size and malignancy but to varying extents, depending on the type of tumor. Thus, except for MCMs, GINS and Cdc45 could also serve as diagnostic and prognostic biomarkers for multiple tumors, which also as a druggable target to treat cancers (Table 5).…”