小柯机器人

新生和已有微小染色体维持蛋白（MCM）之间的平衡可保护基因组复制，这一成果由丹麦哥本哈根大学Jiri Lukas和Kumar Somyajit团队经过不懈努力而取得。相关论文于2020年10月21日在线发表于《自然》杂志。

研究人员发现为了使子细胞维持无错误的DNA复制，其母细胞通过回收与染色质结合的（亲代）MCM以及生成新的（新生）MCM来建立MCM库。尽管所有MCM都可以形成复制前复合物（pre-RC），但母细胞的MCM库是稳定的，并且优先发育为CDC45-MCM-GINS（CMG）解旋酶。相比之下，新生的MCM3-7（而不是MCM2）在细胞质中进行快速蛋白水解，它们的稳定和核易位需要与微染色体维持复合物结合蛋白（MCMBP）（MCM的远源旁系同源物）相互作用。

作为新生MCM的伴侣蛋白，MCMBP通过增加不参与复制起点但调节复制体移动速度以最小化DNA复制过程中错误的pre-RC来保护基因组复制。因此，尽管MCMBP缺失细胞中pre-RC的缺乏并不能整体改变DNA合成，但会增加单个复制体的复制速度和不对称性，从而导致DNA损伤。因此，多余MCM通过限制真核细胞中DNA复制的速度来提高基因组复制的准确性。因此，复制叉速度的改变可能解释为什么即使MCM水平的轻微降低也会破坏基因组的稳定性，并利于肿瘤的发生 。

据悉，MCM是DNA依赖性ATPase，可与复制起点结合并赋予其开启单轮DNA复制的能力。过量的MCM2-7在G1期染色质上组装为pre-RC，其中只有一小部分成为基因组复制所需的生产性CMG解旋酶。尚不清楚为什么细胞会产生这种多余的MCM、如何在多个后代中维持其含量以及为什么即使轻度降低MCM库也会损害基因组复制的完整性。

附：英文原文

Title: Equilibrium between nascent and parental MCM proteins protects replicating genomes

Author: Hana Sedlackova, Maj-Britt Rask, Rajat Gupta, Chunaram Choudhary, Kumar Somyajit, Jiri Lukas

Issue&Volume: 2020-10-21

Abstract: Minichromosome maintenance proteins (MCMs) are DNA-dependent ATPases that bind to replication origins and license them to support a single round of DNA replication. A large excess of MCM2–7 assembles on chromatin in G1 phase as pre-replication complexes (pre-RCs), of which only a fraction become the productive CDC45–MCM–GINS (CMG) helicases that are required for genome duplication1,2,3,4. It remains unclear why cells generate this surplus of MCMs, how they manage to sustain it across multiple generations, and why even a mild reduction in the MCM pool compromises the integrity of replicating genomes5,6. Here we show that, for daughter cells to sustain error-free DNA replication, their mother cells build up a nuclear pool of MCMs both by recycling chromatin-bound (parental) MCMs and by synthesizing new (nascent) MCMs. Although all MCMs can form pre-RCs, it is the parental pool that is inherently stable and preferentially matures into CMGs. By contrast, nascent MCM3–7 (but not MCM2) undergo rapid proteolysis in the cytoplasm, and their stabilization and nuclear translocation require interaction with minichromosome-maintenance complex-binding protein (MCMBP), a distant MCM paralogue7,8. By chaperoning nascent MCMs, MCMBP safeguards replicating genomes by increasing chromatin coverage with pre-RCs that do not participate on replication origins but adjust the pace of replisome movement to minimize errors during DNA replication. Consequently, although the paucity of pre-RCs in MCMBP-deficient cells does not alter DNA synthesis overall, it increases the speed and asymmetry of individual replisomes, which leads to DNA damage. The surplus of MCMs therefore increases the robustness of genome duplication by restraining the speed at which eukaryotic cells replicate their DNA. Alterations in physiological fork speed might thus explain why even a minor reduction in MCM levels destabilizes the genome and predisposes to increased incidence of tumour formation.

DOI: 10.1038/s41586-020-2842-3

Source: https://www.nature.com/articles/s41586-020-2842-3

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