Ribonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication.
Ribonucleotide Reductase Requires Subunit Switching in Hypoxia to Maintain DNA Replication.
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DOI：
10.1016/j.molcel.2017.03.005
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发表时间：
2017-04-20
期刊：
影响因子：
16
通讯作者：
Hammond EM
中科院分区：
文献类型：
--
作者：
Foskolou IP;Jorgensen C;Leszczynska KB;Olcina MM;Tarhonskaya H;Haisma B;D'Angiolella V;Myers WK;Domene C;Flashman E;Hammond EM
暴露于缺氧的细胞经历复制应激，但不积累DNA损伤，表明持续的DNA复制。核糖核苷酸还原酶（RNR）是唯一能够从头合成脱氧核糖核苷酸三磷酸（dNTPs）的酶。然而，氧是哺乳动物RNR（RRM 1/RRM 2和RRM 1/RRM 2B）的重要辅助因子，这使我们质疑缺氧中dNTPs的来源。在这里，我们表明RRM 1/RRM 2B酶能够在缺氧条件下保持活性，因此比RRM 1/RRM 2更有利于保持正在进行的复制并避免DNA损伤的积累。我们发现RRM 2B维持低氧活性的两种不同机制，并确定了RRM 2B中的负责残基。RRM 2B在对肿瘤缺氧的应答中的重要性通过其表达与患者样品中缺氧特征的相关性及其在肿瘤生长和放射抗性中的作用进一步说明。我们的数据提供了对RNR生物学的机制性见解，突出了RRM 2B作为低氧特异性抗癌治疗靶点。RRM 2B在两种细胞模型和患者数据集中响应于缺氧而被诱导，RRM 2B在缺氧条件下保持活性，并且是缺氧中有利的RNR亚基。证明在缺氧条件下，RNR酶的小亚基从RRM 2转换为RRM 2B，以促进核苷酸生产和持续复制。他们鉴定了RRM 2B中负责在缺氧中维持活性的特定残基。
Cells exposed to hypoxia experience replication stress but do not accumulate DNA damage, suggesting sustained DNA replication. Ribonucleotide reductase (RNR) is the only enzyme capable of de novo synthesis of deoxyribonucleotide triphosphates (dNTPs). However, oxygen is an essential cofactor for mammalian RNR (RRM1/RRM2 and RRM1/RRM2B), leading us to question the source of dNTPs in hypoxia. Here, we show that the RRM1/RRM2B enzyme is capable of retaining activity in hypoxia and therefore is favored over RRM1/RRM2 in order to preserve ongoing replication and avoid the accumulation of DNA damage. We found two distinct mechanisms by which RRM2B maintains hypoxic activity and identified responsible residues in RRM2B. The importance of RRM2B in the response to tumor hypoxia is further illustrated by correlation of its expression with a hypoxic signature in patient samples and its roles in tumor growth and radioresistance. Our data provide mechanistic insight into RNR biology, highlighting RRM2B as a hypoxic-specific, anti-cancer therapeutic target. RRM2B is induced in response to hypoxia in both cell models and patient datasets RRM2B retains activity in hypoxic conditions and is the favored RNR subunit in hypoxia Loss of RRM2B has detrimental consequences for cell fate, specifically in hypoxia RRM2B depletion enhanced hypoxic-specific apoptosis and increased radiosensitivity Foskolou et al. demonstrate that in hypoxic conditions the small subunit of the RNR enzyme is switched from RRM2 to RRM2B in order to facilitate nucleotide production and ongoing replication. They identify specific residues within RRM2B that are responsible for maintaining activity in hypoxia.