Mitosis without DNA replication in mammalian somatic cells

Abstract

DNA replication initiates with pre-replication complex (pre-RC) formation at replication origins in G1 (replication origin licensing), followed by activation of a pre-RC subset in the S phase. It has been suggested that a checkpoint prevents S phase entry when too few origins are licensed. Yet, we found that in normal cells, complete DNA synthesis inhibition by overexpression of a non-degradable geminin variant, or by CDT1 silencing prevents DNA replication without inducing any checkpoint. Cells continue cycling and enter mitosis, despite the absence of replicated DNA. Most of these unlicensed cells exit mitosis without dividing and enter senescence; however, about 25% of them successfully divide without previous DNA replication, producing daughter cells with half the normal diploid complement of chromosomes (1C). This suggests a potentially attractive strategy to derive haploid cells from any somatic cell type and unveil undescribed aspects of the coordination between DNA replication and cell division in mammals.