Re-evaluation of Diadenosine Tetraphosphate (Ap(4)A) From a Stress Metabolite to Bona Fide Secondary Messenger.
Re-evaluation of Diadenosine Tetraphosphate (Ap(4)A) From a Stress Metabolite to Bona Fide Secondary Messenger.
复制标题
DOI：
10.3389/fmolb.2020.606807
复制
发表时间：
2020
影响因子：
5
通讯作者：
Copeland NA
中科院分区：
文献类型：
--
作者：
Ferguson F;McLennan AG;Urbaniak MD;Jones NJ;Copeland NA
细胞动态平衡需要适应环境压力。在各种环境和遗传毒性应激下，所有细胞都会产生二核苷多磷酸(Npnns)，其中研究最多的是二腺苷四磷酸(Ap4A)。尽管进行了深入的研究，但这些分子的确切生物学作用仍然难以捉摸。然而，最近的研究已经阐明了这些核苷酸在原核生物和真核生物中的不同和特定的信号机制。本文总结了这些重要的发现，并描述了Ap4A和Ap4N合成的机制，细胞对这些分子水平升高的反应的媒介，以及在没有胁迫的情况下维持低水平所需的水解性机制。细胞内对二核苷酸积累的反应是在“朋友”和“敌人”情景的背景下评估的。“朋友(或警报)假说”认为，ApnN充当真正的第二信使，调节对压力的反应。相反，“敌人”假说认为ApnN和其他NpnN是在严重受损的细胞中由于生理和环境应激而非规范的酶合成而产生的，但并不主动调节缓解的信号通路。此外，我们还将讨论潜在的靶蛋白，并严格评估ApnN在基因表达、免疫反应、DNA复制和DNA修复调节中的新证据支持作用。该领域的最新进展引起了人们的极大兴趣，因为它们首次揭示了一些介导细胞对ApnN反应的分子机制。最后，讨论了未来研究的领域，细胞内ApnN可能但未经证实的作用，以鼓励对受这些核苷酸调控的信号网络的进一步研究。
Cellular homeostasis requires adaption to environmental stress. In response to various environmental and genotoxic stresses, all cells produce dinucleoside polyphosphates (NpnNs), the best studied of which is diadenosine tetraphosphate (Ap4A). Despite intensive investigation, the precise biological roles of these molecules have remained elusive. However, recent studies have elucidated distinct and specific signaling mechanisms for these nucleotides in prokaryotes and eukaryotes. This review summarizes these key discoveries and describes the mechanisms of Ap4A and Ap4N synthesis, the mediators of the cellular responses to increased intracellular levels of these molecules and the hydrolytic mechanisms required to maintain low levels in the absence of stress. The intracellular responses to dinucleotide accumulation are evaluated in the context of the “friend” and “foe” scenarios. The “friend (or alarmone) hypothesis” suggests that ApnN act as bona fide secondary messengers mediating responses to stress. In contrast, the “foe” hypothesis proposes that ApnN and other NpnN are produced by non-canonical enzymatic synthesis as a result of physiological and environmental stress in critically damaged cells but do not actively regulate mitigating signaling pathways. In addition, we will discuss potential target proteins, and critically assess new evidence supporting roles for ApnN in the regulation of gene expression, immune responses, DNA replication and DNA repair. The recent advances in the field have generated great interest as they have for the first time revealed some of the molecular mechanisms that mediate cellular responses to ApnN. Finally, areas for future research are discussed with possible but unproven roles for intracellular ApnN to encourage further research into the signaling networks that are regulated by these nucleotides.
登录
查看更多内容
影响因子：
4.8
作者：
Anashkin, Viktor A.;Salminen, Anu;Baykov, Alexander A.
通讯作者：
Baykov, Alexander A.
影响因子：
2.9
作者：
Barnes, LD;Garrison, PN;Huebner, F
通讯作者：
Huebner, F
影响因子：
5.4
作者：
Chen, Xiaolong;Boonyalai, Nonlawat;Miller, Andrew D.
通讯作者：
Miller, Andrew D.
影响因子：
2.7
作者：
Azhar, M. Ameruddin;Wright, Michael;Miller, Andrew D.
通讯作者：
Miller, Andrew D.
影响因子：
14.8
作者：
Bettendorff, Lucien;Wirtzfeld, Barbara;Wins, Pierre
通讯作者：
Wins, Pierre