Myc and the Replicative CMG Helicase: The Creation and Destruction of Cancer: Myc Over‐Activation of CMG Helicases Drives Tumorigenesis and Creates a Vulnerability in CMGs for Therapeutic Intervention. (20th February 2020)

• Record Type: Journal Article
• Authors: Reed, Damon R.; Alexandrow, Mark G.
• Is Part Of: BioEssays. Volume 42:Number 4(2020:Apr.)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-02-20
• Subjects: Cdc45‐MCM‐GINS helicase -- chemotherapy -- DNA replication -- Myc -- tumorigenesis; Molecular biology -- Periodicals; Cytology -- Periodicals; Developmental biology -- Periodicals; 572.8
• DOI: 10.1002/bies.201900218
• Languages: English
• ISSNs: 0265-9247

Abstract

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. Abstract : Myc is involved in the conversion of mini‐chromosome maintenance hexamer complexes into Cdc45‐MCM‐GINS (CMG) helicases for DNA replication, but too much Myc over‐activates CMG helicases. This reduces the number of unused reserve CMGs necessary for recovery from replicative stresses, promoting tumorigenesis but also creating an exploitable CMG weakness in tumor versus normal cells.