Final checkup of neoplastic DNA replication: Evidence for failure in decision-making at the mitotic cell cycle checkpoint G₁/S

Transcriptional inheritance of cell memory (oversimplified). Parental cell: Transcriptional information on an earlier developmental decision is epigenomically preprocessed and inactivated. Mitosis: The inactivated information is stored in condensed heterochromatin. The parental cell divides into daughter cells both receiving a complete set of stored transcriptional information. Daughter cells: Stored information is either transcriptionally reactivated in decondensed chromatin by epigenomic factors and is ready to participate in the next cell cycle as transcribable signals (left branch). Alternatively, transcriptional signals remain postmitotically inactivated, stored in heterochromatin and will be presented as such to the next mitotic cell division (right branch).

Signal presentation to G₁/S transition of the cell cycle: Hypothesis. G₀ phase: Generation of transcriptional signals—Epigenomic processing of transcriptional information through chromatin modifiers, DNA methylation status, etc. G₀/G₁ transition: Entry of the cell cycle by transcriptional signals. G₁ phase: Signals are identified, filtered, and condensed to a single command (or to a limited number of commands) for presentation to G₁/S transition. G₁/S transition: Final decision-making whether the cell should be allowed to enter S-phase for DNA replication or, alternatively, be rejected for cycle arrest, senescence, or neoplastic transformation.

Transcriptional instability: transitory in cell senescence/cycle arrest vs permanent in neoplastic transformation. Incoming epigenomic signals from histone-mediated chromatin arrangements and DNA methylation are processed during G₁ passage and presented as transcriptional information to parental checkpoint G₁/S for decision-making on DNA replication, see Figure 2. Messages to regular transcriptional reorientation programs (differentiation, cycle arrest, senescence) to nonneoplastic daughter cells seem to be associated with transient transcriptional instabilities (symbolized by the red crescent in the left daughter cell); new levels of transcriptional stability are rapidly established, possibly during G₂/M phase. In a few stem cells, however, failure or abnormal G₁/S decision-making leads to persistence of epigenomic/genomic transcriptional instabilities/deregulations involving entire sets of pathogenetic neoplasm-associated genes (right daughter cell) and may initiate the expression of neoplastic transcription programs, probably over several cell cycles.