Replication-dependent histone biosynthesis is coupled to cell-cycle commitment.
Replication-dependent histone biosynthesis is coupled to cell-cycle commitment.
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DOI：
10.1073/pnas.2100178118
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发表时间：
2021-08-03
影响因子：
11.1
通讯作者：
Spencer SL
中科院分区：
文献类型：
--
作者：
Armstrong C;Spencer SL
目前的想法限制复制依赖性（RD）组蛋白生物合成的细胞周期的S期，与组蛋白的生产开始伴随着DNA复制。这项工作研究了单个人类细胞中RD组蛋白生物合成的细胞周期时间，并表明虽然在S期确实有RD组蛋白生产的爆发，但RD组蛋白生产实际上在G1期开始较早，在细胞周期承诺的点。这些结果表明，出生致力于随后的细胞周期的细胞在启动DNA复制之前建立了一个小的组蛋白库，从而防止基因组完整性的丧失，并且与已经退出细胞周期并且在细胞周期重新进入之前不需要组蛋白合成的细胞不同。目前的复制依赖性（RD）组蛋白生物合成模型假定RD组蛋白基因表达与DNA复制偶联，仅在DNA合成开始后细胞周期的S期发生。然而，RD组蛋白生物合成途径中的几个关键因子被E2 F上调或被CDK 2磷酸化，这表明这些过程可能在细胞周期定型时开始得更早。在这项研究中，我们使用人类细胞的固定和活细胞成像来解决这个问题，揭示了一个混合模型，其中RD组蛋白生物合成首先在G1中启动，然后在细胞周期的S期组蛋白产量大幅增加。这表明了一种机制，通过这种机制，已进入细胞周期的细胞在产生S期所需的大部分必要组蛋白之前，建立了一个初始的小RD组蛋白库，可用于DNA复制的开始。因此，在有丝分裂完成时，在出生时意图通过细胞周期进行并复制其DNA的细胞与选择退出细胞周期并且不立即需要组蛋白合成的细胞之间存在明显的区别。
Current thinking limits replication-dependent (RD) histone biosynthesis to S phase of the cell cycle, with histone production initiated concomitantly with DNA replication. This work examines the cell-cycle timing of RD histone biosynthesis in single human cells and shows that while there is indeed a burst of RD histone production in S phase, RD histone production actually begins earlier in G1, at the point of cell-cycle commitment. These results demonstrate that cells born committed to the subsequent cell cycle build up a small pool of histones before initiating DNA replication, thereby safeguarding against a loss of genome integrity, and are distinct from cells that have exited the cell cycle and do not require histone synthesis until cell-cycle reentry. The current model of replication-dependent (RD) histone biosynthesis posits that RD histone gene expression is coupled to DNA replication, occurring only in S phase of the cell cycle once DNA synthesis has begun. However, several key factors in the RD histone biosynthesis pathway are up-regulated by E2F or phosphorylated by CDK2, suggesting these processes may instead begin much earlier, at the point of cell-cycle commitment. In this study, we use both fixed- and live-cell imaging of human cells to address this question, revealing a hybrid model in which RD histone biosynthesis is first initiated in G1, followed by a strong increase in histone production in S phase of the cell cycle. This suggests a mechanism by which cells that have committed to the cell cycle build up an initial small pool of RD histones to be available for the start of DNA replication, before producing most of the necessary histones required in S phase. Thus, a clear distinction exists at completion of mitosis between cells that are born with the intention of proceeding through the cell cycle and replicating their DNA and cells that have chosen to exit the cell cycle and have no immediate need for histone synthesis.
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