Theory of the organization of the mammalian cell and viral DNA genomes and the mechanism of carcinogenesis

Abstract

The present theory suggests that different families of DNA molecules are present in the mammalian cell DNA genome, which are characterized by the presence or absence of poly-dG · dC or poly-dA §d dT sequences, respectively. The control of the transcription of RNA molecules from the different DNA classes might be an independent process which is carried out by different RNA polymerases. Furthermore, the DNA molecules with poly-dG · dC sequences are transcribed during the S phase of the mammalian cell, while the DNA which contains poly-dA · dT sequences are transcribed during the G 2 phase, along with the DNA which contains the information for ribosomal RNA. Thus, the life cycle of a eukaryocyte is regulated by the transcription of different classes of RNA at different stages of the cell cycle. The viral DNA genome resembles in its organization the cell DNA and it contains poly-dG · dC and poly-dA · dT sequences. The genes which are initially transcribed from the viral DNA genome are those adjacent to a polycytidine sequence in the transcribing DNA strand. The translation of these messenger RNA species is followed by the transcription of other viral genes which are situated in the DNA genome adjacent to polydeoxythymidine sequences in the transcribing strand, resulting in the synthesis of “late” viral mRNA species. Cells infected with a tumorogenic DNA virus might enable the interaction of the poly-dG · dC sequences present in the viral DNA genome with the poly-dG · dC regions in the chromosomal DNA. After one division cycle the viral DNA is integrated into the host DNA genome in the cellular chromosomal DNA which contains poly-dG · dC regions. The cellular RNA polymerase which transcribes the chromosomal DNA with the poly-dG · dC sequences can also transcribe mRNA from the viral genes adjacent to the poly-dG · dC sequences in the integrated viral DNA, but not from the genes which are initiated at poly-dA · dT sequences. In their ability to interact with polydeoxyguanidine sequences in the DNA of specific chromosomes, chemical carcinogens and X-irradiation might resemble the tumorogenic DNA viruses. Therefore, it is suggested that any change which occurs at the poly-dG · dC sequences in the susceptible chromosomal DNA might lead to the regaining by the cell of the ability to grow and multiply. Finally, the DNA product of RNA tumor viruses might have poly-dG · dC sequences which might participate in the integration of the viral DNA into the cell DNA. The present theory provides an approach to the organization of the mammalian cell DNA genome and suggests a possible mechanism for cell transformation which involves polynucleotide sequences in the DNA situated next to the genes. It is hoped that this approach will help in the development of additional tools for the study of the mechanism that controls cell growth and carcinogenesis.