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Equilibrium between nascent and parental MCM proteins protects replicating genomes

机译：新生和亲本MCM蛋白质之间的均衡保护复制基因组

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摘要

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 duplication~(1-4). 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 genomes~(5,6). 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 paralogue~(7,8). 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.
机译：小核糖组体维持蛋白（MCMS）是DNA依赖性的ATP酶，其与复制起源结合，并许可它们以支持一轮DNA复制。大量过量的MCM2-7在G1相中组合在G1相中作为预复制复合物（预rcs），其中仅部分是基因组重复所需的生产CDC45-MCM-GINS（CMG）螺旋酶〜（1 -4）。它仍然尚不清楚为什么细胞产生这种盈余的MCM，他们如何管理跨多种世代维持它，以及为什么MCM池中的轻度减少损害了复制基因组的完整性〜（5,6）。在这里，我们表明，对于女儿细胞来维持无误的DNA复制，它们的母细胞通过再循环染色质（亲本）MCM和通过合成新（新生）MCM来构建核池。虽然所有MCM都可以形成RCS前，但它是固有的稳定性，优先成熟的父母池。相比之下，新生MCM3-7（但不是MCM2）在细胞质中进行快速蛋白水解，它们的稳定化和核转移需要与微微核糖组维持复合蛋白（MCMBP）的相互作用，远处MCM级级蛋白〜（7,8）。通过陪伴Nascent MCMS，MCMBP通过增加染色质覆盖率随着不参与复制的前rcs来保护基因组来保障基因组，但调整额外的运动速度，以最小化DNA复制期间的误差。因此，尽管MCMBP缺陷细胞中RCS的缺乏整体不改变DNA合成，但它增加了个体重复的速度和不对称性，这导致DNA损伤。因此，MCMS的盈余通过限制真核细胞复制其DNA的速度来增加基因组重复的稳健性。因此，生理叉速的改变可能会解释为什么MCM水平的轻微降低使基因组稳定并易于增加肿瘤形成的发病率。

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  • 来源
    《Nature》 |2020年第7833期|297-302|共6页
  • 作者

    Hana Sedlackova; Maj-Britt Rask; Rajat Gupta; Chunaram Choudhary; Kumar Somyajit; Jiri Lukas;

  • 作者单位

    Protein Signaling Program Novo Nordisk Foundation Center for Protein Research Faculty of Health and Medical Sciences University of Copenhagen;

    Protein Signaling Program Novo Nordisk Foundation Center for Protein Research Faculty of Health and Medical Sciences University of Copenhagen;

    Proteomics Program Novo Nordisk Foundation Center for Protein Research Faculty of Health and Medical Sciences University of Copenhagen;

    Proteomics Program Novo Nordisk Foundation Center for Protein Research Faculty of Health and Medical Sciences University of Copenhagen;

    Protein Signaling Program Novo Nordisk Foundation Center for Protein Research Faculty of Health and Medical Sciences University of Copenhagen;

    Protein Signaling Program Novo Nordisk Foundation Center for Protein Research Faculty of Health and Medical Sciences University of Copenhagen;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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