Transcriptional control of DNA replication licensing by Myc

Sci Rep. 2013 Dec 6:3:3444. doi: 10.1038/srep03444.

Abstract

The c-myc protooncogene encodes the Myc transcription factor, a global regulator of fundamental cellular processes. Deregulation of c-myc leads to tumorigenesis, and c-myc is an important driver in human cancer. Myc and its dimerization partner Max are bHLH-Zip DNA binding proteins involved in transcriptional regulation of target genes. Non-transcriptional functions have also been attributed to the Myc protein, notably direct interaction with the pre-replicative complex (pre-RC) controlling the initiation of DNA replication. A key component of the pre-RC is the Cdt1 protein, an essential factor in origin licensing. Here we present data suggesting that the CDT1 gene is a transcriptional target of the Myc-Max complex. Expression of the CDT1 gene in v-myc-transformed cells directly correlates with myc expression. Also, human tumor cells with elevated c-myc expression display increased CDT1 expression. Occupation of the CDT1 promoter by Myc-Max is demonstrated by chromatin immunoprecipitation, and transactivation by Myc-Max is shown in reporter assays. Ectopic expression of CDT1 leads to cell transformation. Our results provide a possible direct mechanistic link of Myc's canonical function as a transcription factor to DNA replication. Furthermore, we suggest that aberrant transcriptional activation of CDT1 by deregulated myc alleles contributes to the genomic instabilities observed in tumor cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / genetics
  • Cell Line
  • Cell Line, Transformed
  • Cell Transformation, Neoplastic / genetics
  • Chickens
  • DNA Replication*
  • Gene Expression Regulation*
  • Gene Order
  • Humans
  • Molecular Sequence Data
  • Promoter Regions, Genetic
  • Protein Binding
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Transcription, Genetic*
  • Transcriptional Activation

Substances

  • Cell Cycle Proteins
  • Proto-Oncogene Proteins c-myc