Genome Research
Abstract
DNA replication perturbs the dosage balance among genes; at the mid-S phase, early-replicating genes have doubled their copies while late-replicating ones have not. Dosage imbalance among genes, especially within members of a protein complex, is toxic to cells. However, the molecular mechanisms that cells deal with such imbalance remain not fully understood. Here, we validate at the genomic scale that the dosage between early- and late-replicating genes are imbalanced in HeLa cells. We propose the synchronized replication hypothesis that 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 mainly in fast-proliferating cells such as embryonic stem cells and cancer cells. We find that 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. Taken together, our study reveals that the demand for dosage balance during S phase plays an important role in the optimization of the replication-timing program; this selection is relaxed during differentiation as the cell cycle prolongs, and restored during tumorigenesis as the cell cycle shortens.
| 论文编号: | DOI:10.1101/gr.254342.119 |
| 论文题目: | Synchronized Replication of Genes Encoding the Same Protein Complex in Fast-proliferating Cells |
| 英文论文题目: | Synchronized Replication of Genes Encoding the Same Protein Complex in Fast-proliferating Cells |
| 第一作者: | Ying Chen, Ke Li, Xiao Chu, Lucas B. Carey, and Wenfeng Qian |
| 英文第一作者: | Ying Chen, Ke Li, Xiao Chu, Lucas B. Carey, and Wenfeng Qian |
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| 发表年度: | 2019-12-06 |
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| 摘要: | DNA replication perturbs the dosage balance among genes; at the mid-S phase, early-replicating genes have doubled their copies while late-replicating ones have not. Dosage imbalance among genes, especially within members of a protein complex, is toxic to cells. However, the molecular mechanisms that cells deal with such imbalance remain not fully understood. Here, we validate at the genomic scale that the dosage between early- and late-replicating genes are imbalanced in HeLa cells. We propose the synchronized replication hypothesis that 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 mainly in fast-proliferating cells such as embryonic stem cells and cancer cells. We find that 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. Taken together, our study reveals that the demand for dosage balance during S phase plays an important role in the optimization of the replication-timing program; this selection is relaxed during differentiation as the cell cycle prolongs, and restored during tumorigenesis as the cell cycle shortens. |
| 英文摘要: | DNA replication perturbs the dosage balance among genes; at the mid-S phase, early-replicating genes have doubled their copies while late-replicating ones have not. Dosage imbalance among genes, especially within members of a protein complex, is toxic to cells. However, the molecular mechanisms that cells deal with such imbalance remain not fully understood. Here, we validate at the genomic scale that the dosage between early- and late-replicating genes are imbalanced in HeLa cells. We propose the synchronized replication hypothesis that 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 mainly in fast-proliferating cells such as embryonic stem cells and cancer cells. We find that 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. Taken together, our study reveals that the demand for dosage balance during S phase plays an important role in the optimization of the replication-timing program; this selection is relaxed during differentiation as the cell cycle prolongs, and restored during tumorigenesis as the cell cycle shortens. |
| 刊物名称: | Genome Research |
| 英文刊物名称: | Genome Research |
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| 其它备注: | Ying Chen, Ke Li, Xiao Chu, Lucas B. Carey, and Wenfeng Qian. Synchronized Replication of Genes Encoding the Same Protein Complex in Fast-proliferating Cells. Genome Research. DOI:10.1101/gr.254342.119 |
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