c-Myc directly regulates the transcription of the NBS1 gene involved in DNA double-strand break repair.
The c-myc proto-oncogene encodes a ubiquitous transcription factor involved in the control of cell growth and implicated in inducing tumorigenesis. Understanding the function of c-Myc and its role in cancer depends upon the identification of c-Myc target genes. Nijmegen breakage syndrome (NBS) is a chromosomal-instability syndrome associated with cancer predisposition, radiosensitivity, and chromosomal instability. The NBS gene product, NBS1 (p95 or nibrin), is a part of the hMre11 complex, a central player associated with double-strand break (DSB) repair. NBS1 contains domains characteristic for proteins involved in DNA repair, recombination, and replication. Here we show that c-Myc directly activates NBS1. c-Myc-mediated induction of NBS1 gene transcription occurs in different tissues, is independent of cell proliferation, and is mediated by a c-Myc binding site in the intron 1 region of NBS1 gene. Overexpression of NBS1 in Rat1a cells increased cell proliferation. These results indicate that NBS1 is a direct transcriptional target of c-Myc and links the function of c-Myc to the regulation of DNA DSB repair pathway operating during DNA replication.
Chiang
Yu-Chi
YC
Department of Medical Genetics, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Teng
Shu-Chun
SC
Su
Yi-Ning
YN
Hsieh
Fon-Jou
FJ
Wu
Kou-Juey
KJ
D016475:3T3 Cells; D000818:Animals; D001665:Binding Sites; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000502:physiology; D002455:Cell Division; D002460:Cell Line; D002461:Cell Line, Transformed; D003001:Cloning, Molecular; D004247:DNA / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins; D017353:Gene Deletion; D015870:Gene Expression; D005786:Gene Expression Regulation; D006801:Humans; D007438:Introns; D008156:Luciferases / Q000235:genetics; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology; D011401:Promoter Regions, Genetic; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc / Q000494:pharmacology / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D014158:Transcription, Genetic; D014162:Transfection
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; C112156:NBN protein, human; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D000090063:Proto-Oncogene Mas; D016271:Proto-Oncogene Proteins c-myc; D011993:Recombinant Fusion Proteins; D004247:DNA; D008156:Luciferases