c-Myc initiates illegitimate replication of the ribonucleotide reductase R2 gene.
The mechanisms through which the oncoprotein c-Myc initiates locus-specific gene amplification are not understood. When analysing the initiation mechanism of c-Myc-dependent amplification of the mouse ribonucleotide reductase R2 (R2) gene, we observe c-Myc-dependent initiation of illegitimate DNA replication of the R2 gene. We demonstrate multiple simultaneous c-Myc-induced R2 replication forks, whereas R2 normally replicates with a single fork. In contrast, cyclin C replicates with only a single replication fork irrespective of c-Myc deregulation. In addition to de novo replication forks, c-Myc also initiates bi-allelic replication of R2, abrogating its normal mono-allelic replication pattern. Moreover, several chromosomal regions also display c-Myc-induced illegitimate replication profiles. Thus, c-Myc can act as an illegitimate replication-licensing factor that promotes de novo replication initiation and illegitimate replication timing that adversely impacts upon genomic stability.
Kuschak
T I
TI
Department of Microbiology, Manitoba Institute of Cell Biology, The University of Manitoba, 675 McDermot Ave., Winnipeg, MB, R3E 0V9, Canada.
Kuschak
B C
BC
Taylor
C L
CL
Wright
J A
JA
Wiener
F
F
Mai
S
S
D000483:Alleles; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; D001973:Bromodeoxyuridine / Q000032:analysis; D002453:Cell Cycle / Q000235:genetics; D002478:Cells, Cultured; D002871:Chromosome Banding; D002875:Chromosomes / Q000235:genetics / Q000648:ultrastructure; D056745:Cyclin C; D016213:Cyclins / Q000235:genetics; D004261:DNA Replication / Q000502:physiology; D004268:DNA-Binding Proteins / Q000737:chemistry; D019281:Dimerization; D015180:Electrophoresis, Gel, Two-Dimensional; D024202:Electrophoretic Mobility Shift Assay; D005784:Gene Amplification; D005786:Gene Expression Regulation; D016259:Genes, myc; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D008940:Mitotic Index; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000502:physiology; D011995:Recombination, Genetic / Q000235:genetics / Q000502:physiology*; D012045:Regulatory Sequences, Nucleic Acid; D012262:Ribonucleoside Diphosphate Reductase / Q000235:genetics*; D014157:Transcription Factors; D014162:Transfection
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; C503674:CCNC protein, human; C503675:Ccnc protein, mouse; D056745:Cyclin C; D016213:Cyclins; D004268:DNA-Binding Proteins; C499330:MAX protein, human; C067850:Myc associated factor X; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C068422:Max protein, mouse; C093713:ribonucleotide reductase M2; D012262:Ribonucleoside Diphosphate Reductase; D001973:Bromodeoxyuridine