Selection for synchronized replication of genes encoding the same protein complex during tumorigenesis

DNA replication alters the dosage balance among genes; at the mid-S phase, early-replicating genes have doubled their copies while late-replicating genes have not. Dosage imbalance among proteins, especially within members of a protein complex, is toxic to cells. Here, we propose the synchronized replication hypothesis: genes sensitive to stoichiometric relationships will be replicated simultaneously to maintain stoichiometry. In support of this hypothesis, we observe that genes encoding the same protein complex have similar replication timing, but surprisingly, only in fast-proliferating cells such as embryonic stem cells and cancer cells. The synchronized replication observed in cancer cells, but not in slow-proliferating differentiated cells, is due to convergent evolution during tumorigenesis that restores synchronized replication timing within protein complexes. Collectively, our study reveals that the selection for dosage balance during S phase plays an important role in the optimization of the replication-timing program; that this selection is relaxed during differentiation as the cell cycle is elongated, and restored as the cell cycle shortens during tumorigenesis.