Corcoles-Saez Isaac, Ferat Jean-Luc, Costanzo Michael, Boone Charles M, Cha Rita S
School of Medical Sciences, North West Cancer Research Institute, Bangor University, Deniol Road, Bangor, LL57 2UW, United Kingdom.
Institute of Integrative Biology of the Cell (I2BC), Avenue de la Terrasse, Paris, France.
Microb Cell. 2019 May 20;6(6):286-294. doi: 10.15698/mic2019.06.680.
Ribonucleotide reductase (RNR) is an essential holoenzyme required for synthesis of dNTPs. The genome encodes for two catalytic subunits, Rnr1 and Rnr3. While Rnr1 is required for DNA replication and DNA damage repair, the function(s) of Rnr3 is unknown. Here, we show that carbon source, an essential nutrient, impacts Rnr1 and Rnr3 abundance: Non-fermentable carbon sources or limiting concentrations of glucose down regulate Rnr1 and induce Rnr3 expression. Oppositely, abundant glucose induces Rnr1 expression and down regulates Rnr3. The carbon source dependent regulation of Rnr3 is mediated by Mec1, the budding yeast ATM/ATR checkpoint response kinase. Unexpectedly, this regulation is independent of all currently known components of the Mec1 DNA damage response network, including Rad53, Dun1, and Tel1, implicating a novel Mec1 signalling axis. Δ leads to growth defects under respiratory conditions and rescues temperature sensitivity conferred by the absence of Tom6, a component of the mitochondrial TOM (translocase of outer membrane) complex responsible for mitochondrial protein import. Together, these results unveil involvement of Rnr3 in mitochondrial functions and Mec1 in mediating the carbon source dependent regulation of Rnr3.
核糖核苷酸还原酶（RNR）是合成脱氧核苷酸三磷酸（dNTPs）所必需的一种全酶。基因组编码两种催化亚基，即Rnr1和Rnr3。虽然Rnr1是DNA复制和DNA损伤修复所必需的，但Rnr3的功能尚不清楚。在此，我们表明碳源作为一种必需营养素，会影响Rnr1和Rnr3的丰度：不可发酵的碳源或有限浓度的葡萄糖会下调Rnr1并诱导Rnr3表达。相反，丰富的葡萄糖会诱导Rnr1表达并下调Rnr3。Rnr3的碳源依赖性调控由芽殖酵母ATM/ATR检查点反应激酶Mec1介导。出乎意料的是，这种调控独立于Mec1 DNA损伤反应网络目前所有已知的组分，包括Rad53、Dun1和Tel1，这暗示了一种新的Mec1信号轴。Δ在呼吸条件下导致生长缺陷，并挽救了因缺乏Tom6（线粒体TOM（外膜转位酶）复合物的一个组分，负责线粒体蛋白导入）所赋予的温度敏感性。总之，这些结果揭示了Rnr3参与线粒体功能以及Mec1介导Rnr3的碳源依赖性调控。
