Non-transcriptional control of DNA replication by c-Myc.
The c-Myc proto-oncogene encodes a transcription factor that is essential for cell growth and proliferation and is broadly implicated in tumorigenesis. However, the biological functions required by c-Myc to induce oncogenesis remain elusive. Here we show that c-Myc has a direct role in the control of DNA replication. c-Myc interacts with the pre-replicative complex and localizes to early sites of DNA synthesis. Depletion of c-Myc from mammalian (human and mouse) cells as well as from Xenopus cell-free extracts, which are devoid of RNA transcription, demonstrates a non-transcriptional role for c-Myc in the initiation of DNA replication. Overexpression of c-Myc causes increased replication origin activity with subsequent DNA damage and checkpoint activation. These findings identify a critical function of c-Myc in DNA replication and suggest a novel mechanism for its normal and oncogenic functions.
Dominguez-Sola
David
D
Institute for Cancer Genetics, Department of Genetics and Development and Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York 10032, USA.
Ying
Carol Y
CY
Grandori
Carla
C
Ruggiero
Luca
L
Chen
Brenden
B
Li
Muyang
M
Galloway
Denise A
DA
Gu
Wei
W
Gautier
Jean
J
Dalla-Favera
Riccardo
R
D000818:Animals; D002457:Cell Extracts; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D004249:DNA Damage / Q000235:genetics; D004261:DNA Replication / Q000235:genetics*; D005347:Fibroblasts; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D018741:Replication Origin / Q000235:genetics*; D014158:Transcription, Genetic; D014981:Xenopus
D002457:Cell Extracts; C000715470:MAS1 protein, human; D046912:Multiprotein Complexes; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc