The increase in cell death rates in caloric restricted cells of the yeast helicase mutant rrm3 is Sir complex dependent.
The increase in cell death rates in caloric restricted cells of the yeast helicase mutant rrm3 is Sir complex dependent.
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DOI：
10.1038/s41598-023-45125-z
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发表时间：
2023-10-19
影响因子：
4.6
通讯作者：
Singh, Sukhwinder
中科院分区：
文献类型：
--
作者：
Ivessa, Andreas S.;Singh, Sukhwinder
热量限制（CR），即在不营养不良的情况下减少热量摄入，通常可以延长寿命并改善组织完整性。本报告的重点是核基因组不稳定性与饮食限制及其对细胞存活的影响之间的关系。我们证明了基因组不稳定性酵母突变体rrm3的细胞存活率在代谢限制条件下发生变化。Rrm3是一种DNA解旋酶，在缺乏Rrm3的情况下，染色体复制减慢（并可能停止），在超过1400个自然暂停位点（包括核糖体DNA和tRNA基因内的位点），染色体复制速率增加。与野生型（WT）相比，rrm3突变体细胞在含有正常葡萄糖水平（即2%）的生长培养基中具有较低的细胞死亡率，而在CR生长条件下，rrm3突变体的细胞死亡率增加到高于WT的水平。当细胞从含有2%葡萄糖的生长培养基转移到CR培养基时，rrm3突变体的细胞死亡率增加需要沉默信息调节（Sir）蛋白复合物和线粒体氧化应激。Rad53检查点蛋白在rrm3突变体中高度磷酸化，以响应含有2%葡萄糖的生长培养基中的基因组不稳定性。CR作用下，rrm3突变体中的Rad53磷酸化以sir复合物依赖的方式大量降低。由于CR是化疗期间的一种辅助治疗，可能针对癌细胞的基因组不稳定性，我们的研究可能会进一步了解如何改进这些治疗策略。
Calorie restriction (CR), which is a reduction in calorie intake without malnutrition, usually extends lifespan and improves tissue integrity. This report focuses on the relationship between nuclear genomic instability and dietary-restriction and its effect on cell survival. We demonstrate that the cell survival rates of the genomic instability yeast mutant rrm3 change under metabolic restricted conditions. Rrm3 is a DNA helicase, chromosomal replication slows (and potentially stalls) in its absence with increased rates at over 1400 natural pause sites including sites within ribosomal DNA and tRNA genes. Whereas rrm3 mutant cells have lower cell death rates compared to wild type (WT) in growth medium containing normal glucose levels (i.e., 2%), under CR growth conditions cell death rates increase in the rrm3 mutant to levels, which are higher than WT. The silent-information-regulatory (Sir) protein complex and mitochondrial oxidative stress are required for the increase in cell death rates in the rrm3 mutant when cells are transferred from growth medium containing 2% glucose to CR-medium. The Rad53 checkpoint protein is highly phosphorylated in the rrm3 mutant in response to genomic instability in growth medium containing 2% glucose. Under CR, Rad53 phosphorylation is largely reduced in the rrm3 mutant in a Sir-complex dependent manner. Since CR is an adjuvant treatment during chemotherapy, which may target genomic instability in cancer cells, our studies may gain further insight into how these therapy strategies can be improved.
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DOI：
10.1126/science.1173635
发表时间：
2009-07-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Colman RJ;Anderson RM;Johnson SC;Kastman EK;Kosmatka KJ;Beasley TM;Allison DB;Cruzen C;Simmons HA;Kemnitz JW;Weindruch R
通讯作者：
Weindruch R
影响因子：
10.5
作者：
Azvolinsky, Anna;Dunaway, Stephen;Zakian, Virginia A.
通讯作者：
Zakian, Virginia A.
DOI：
10.1073/pnas.94.26.14361
发表时间：
1997-12-23
影响因子：
11.1
作者：
Cohen-Fix, O;Koshland, D
通讯作者：
Koshland, D
影响因子：
64.5
作者：
Ciosk, R;Zachariae, W;Nasmyth, K
通讯作者：
Nasmyth, K
影响因子：
64.5
作者：
BREWER, BJ;LOCKSHON, D;FANGMAN, WL
通讯作者：
FANGMAN, WL