Quiescent human diploid cells can inhibit entry into S phase in replicative nuclei in heterodikaryons

Abstract

Serum-deprived quiescent human diploid cells (HDC) were fused to replicative HDC, and DNA synthesis was monitored in the resulting heterodikaryons. Quiescent HDC had an inhibitory effect on DNA synthesis in replicative HDC nuclei in heterodikaryons. The timing of the inhibitory effect suggests that entry into S phase was inhibited but ongoing DNA synthesis was not inhibited in the replicative HDC nuclei. When quiescent HDC were fused to T98G human glioblastoma cells or SUSM-1 chemically transformed human cells, entry into S phase was similarly inhibited. However, when quiescent HDC were fused to simian virus 40-transformed human cells, adenovirus 5-transformed human cells, or HeLa cells, DNA synthesis was induced in the quiescent HDC nuclei. A simple hypothesis to explain these results is that quiescent HDC contain an inhibitor of entry into S phase. Transformed cells with a dominant replicative phenotype may have gained a factor that overrides the putative inhibitor, perhaps through viral transformation, whereas recessive transformed cells may ahve lost the normal inhibitory mechanism, perhaps through mutation. Senescent HDC behave like quiescent HDC in heterodikaryons formed with the same types of replicative cells, which suggest that senescent HDC and quiescent HDC share elements of a common mechanism for cessation of proliferation.