Myc-driven chromatin accessibility regulates Cdc45 assembly into CMG helicases

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. Nepon-Sixt, Bryant, and Alexandrow show that Myc increases the chromatin accessibility through Myc-Box II, activating Cdc45-MCM-GINS helicases at Myc-targeted sites. This study highlights a non-transcriptional role for Myc in over-activating DNA replication, providing insight into Myc-driven tumorigenesis.

• Publication year

  2019

• Venue

  Communications Biology

• Publication date

  2019-03-22

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1038/s42003-019-0353-2PMID 31924949PMCID 6430796
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar

• No claims are published for this paper.

• No concepts are published for this paper.

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