In cancer cells, abnormal methylation patterns of DNA sequences are often present. By examining the role of the PML-RAR fusion gene, a well-studied translocation in leukemia, Di Croce et al. demonstrate that transcriptional silencing in cancer cells can occur through the recruitment of a DNA methyltransferase (Dnmt) by the PML-RAR fusion protein. Recruitment of Dnmts results in the hypermethylation of a PML-RAR target gene, RARβ2. In the presence of PML-RAR and Dnmt, cell differentiation was blocked, but this block could be overcome by administration of retinoic acid. Hence, transcription factors associated with neoplasia can function in methylation-linked silencing of genes important for growth and differentiation. Furthermore, the work shows that a genetic change in cancer can induce epigenetic gene silencing.
L. Di Croce, V. A. Raker, M. Corsaro, F. Fazi, M. Fanelli, M. Faretta, F. Fuks, F. Lo Coco, T. Kouzarides, C. Nervi, S. Minucci, P. G. Pelicci, Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295, 1079-1082 (2002). [Abstract] [Full Text]