Controlled protein degradation regulates ribonucleotide reductase activity in proliferating mammalian cells during the normal cell cycle and in response to DNA damage and replication blocks
Controlled protein degradation regulates ribonucleotide reductase activity in proliferating mammalian cells during the normal cell cycle and in response to DNA damage and replication blocks
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DOI：
10.1074/jbc.m000799200
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发表时间：
2000-06-09
影响因子：
4.8
通讯作者：
Thelander, L
中科院分区：
文献类型：
--
作者：
Chabes, A;Thelander, L
核糖核苷酸还原酶（RNR）在DNA复制和DNA修复过程中所需的脱氧核糖核苷三磷酸的形成和最佳水平的控制中起着核心作用。哺乳动物RNR由两个不相同的亚基组成，即蛋白R1和R2，在哺乳动物细胞周期中，限制性R2蛋白的水平控制着RNR的整体活性，在G(1)期检测不到，在S期增加。我们发现，在增殖的哺乳动物细胞中，R2基因的转录在S期开始时被激活，在6-7小时后达到最大值，然后下降。令人惊讶的是，DNA损伤和复制阻断既没有增加也没有延长S期R2启动子的活性。相反，哺乳动物酶的细胞周期活性是由R2蛋白的S期/ DNA损伤特异性稳定控制的，这种稳定在细胞进入有丝分裂之前是有效的。
Ribonucleotide reductase (RNR) plays a central role in the formation and control of the optimal levels of deoxyribonucleoside triphosphates, which are required for DNA replication and DNA repair processes. Mammalian RNRs are composed of two nonidentical subunits, proteins R1 and R2, The levels of the limiting R2 protein control overall RNR activity during the mammalian cell cycle, being undetectable in G(1) phase and increasing in S phase. We show that in proliferating mammalian cells, the transcription of the R2 gene, once activated in the beginning of S phase, reaches its maximum 6-7 h later and then declines. Surprisingly, DNA damage and replication blocks neither increase nor prolong the R2 promoter activity in S phase. Instead, the cell cycle activity of the mammalian enzyme is controlled by an S phase/ DNA damage-specific stabilization of the R2 protein, which is effective until cells pass into mitosis.