Pyruvate kinase, a metabolic sensor powering glycolysis, drives the metabolic control of DNA replication.
Pyruvate kinase, a metabolic sensor powering glycolysis, drives the metabolic control of DNA replication.
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DOI：
10.1186/s12915-022-01278-3
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发表时间：
2022-04-13
期刊：
影响因子：
5.4
通讯作者：
Janniere, Laurent
中科院分区：
文献类型：
--
作者：
Horemans, Steff;Pitoulias, Matthaios;Holland, Alexandria;Pateau, Emilie;Lechaplais, Christophe;Ekaterina, Dariy;Perret, Alain;Soultanas, Panos;Janniere, Laurent
关键词：
在所有生物体中，DNA复制在广泛的生长条件下被精细地调节，以在细胞分裂之前实现及时和准确的基因组复制。这种调控的失败会导致DNA损伤，对细胞活力和人类健康（包括癌症）造成潜在的灾难性后果。为了应对这些威胁，细胞使用众所周知的机制严格控制复制起始。它们还通过一个鲜为人知的过程将DNA合成与营养丰富度和生长速度结合起来，这个过程被认为涉及中央碳代谢。其中一个过程可能涉及跨物种保守的丙酮酸激酶（PykA），它催化糖酵解的最后反应。在这里，我们研究了PykA在调节模型系统枯草芽孢杆菌DNA复制中的作用。通过分析枯草芽孢杆菌PykA的催化（Cat）和c端（PEPut）结构域突变体，我们发现了PykA在生长中不需要的条件下的复制表型。这些表型独立于突变对PykA催化活性的影响，并且与代谢组的显着变化无关。PEPut作为一种营养依赖的起始抑制剂，而Cat作为复制叉速度的刺激物。即使在完全精通已知复制控制功能的细胞中，PEPut或Cat复制功能的破坏也会显著影响细胞周期和复制时间。在体外，PykA通过功能相互作用调节复制起始和延伸所必需的酶的活性。进一步的实验表明，PEPut调控PykA活性，而对PykA催化活性调控重要的Cat和PEPut决定因素对PykA驱动的复制功能也很重要。我们从我们的研究结果中推断，PykA代表了一个新的跨物种复制控制调节剂家族，通过涉及PykA催化活性的调节决定因素的机制驱动复制的代谢控制。由于PykA复制功能的破坏会导致严重的复制缺陷，我们认为这个新的通用复制调节因子家族的功能障碍可能为遗传不稳定和致癌铺平了道路。在线版本包含补充材料，可在10.1186/s12915-022-01278-3获得。
In all living organisms, DNA replication is exquisitely regulated in a wide range of growth conditions to achieve timely and accurate genome duplication prior to cell division. Failures in this regulation cause DNA damage with potentially disastrous consequences for cell viability and human health, including cancer. To cope with these threats, cells tightly control replication initiation using well-known mechanisms. They also couple DNA synthesis to nutrient richness and growth rate through a poorly understood process thought to involve central carbon metabolism. One such process may involve the cross-species conserved pyruvate kinase (PykA) which catalyzes the last reaction of glycolysis. Here we have investigated the role of PykA in regulating DNA replication in the model system Bacillus subtilis. On analysing mutants of the catalytic (Cat) and C-terminal (PEPut) domains of B. subtilis PykA we found replication phenotypes in conditions where PykA is dispensable for growth. These phenotypes are independent from the effect of mutations on PykA catalytic activity and are not associated with significant changes in the metabolome. PEPut operates as a nutrient-dependent inhibitor of initiation while Cat acts as a stimulator of replication fork speed. Disruption of either PEPut or Cat replication function dramatically impacted the cell cycle and replication timing even in cells fully proficient in known replication control functions. In vitro, PykA modulates activities of enzymes essential for replication initiation and elongation via functional interactions. Additional experiments showed that PEPut regulates PykA activity and that Cat and PEPut determinants important for PykA catalytic activity regulation are also important for PykA-driven replication functions. We infer from our findings that PykA typifies a new family of cross-species replication control regulators that drive the metabolic control of replication through a mechanism involving regulatory determinants of PykA catalytic activity. As disruption of PykA replication functions causes dramatic replication defects, we suggest that dysfunctions in this new family of universal replication regulators may pave the path to genetic instability and carcinogenesis. The online version contains supplementary material available at 10.1186/s12915-022-01278-3.
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影响因子：
--
作者：
Burnell JN
通讯作者：
Burnell JN
影响因子：
3.2
作者：
Bipatnath, M;Dennis, PP;Bremer, H
通讯作者：
Bremer, H
DOI：
10.1073/pnas.1811971115
发表时间：
2018-10-23
影响因子：
11.1
作者：
Brunk, Elizabeth;Chang, Roger L.;Lewis, Nathan E.
通讯作者：
Lewis, Nathan E.
影响因子：
56.9
作者：
Dervyn, E;Suski, C;Ehrlich, SD
通讯作者：
Ehrlich, SD
影响因子：
7.7
作者：
Berge, Matthieu;Pezzatti, Julian;Viollier, Patrick H.
通讯作者：
Viollier, Patrick H.