|
All I's on the RADAR: role of ADAR in gene regulation. |核心内容：
腺苷 adenosine [əˈdenəˌsin]
ATP 目前已知A-to-I编辑参与免疫系统的调节、RNA剪接、蛋白质重新编码、microRNA生物发生和异染色质的形成。 编辑发生在双链RNA区域内，特别是在反向Alu重复序列中，并与许多疾病有关，包括癌症、神经疾病和代谢综合征。 然而，RNA编辑在转录组的很大一部分中的重要性仍不清楚。 在这里，我们回顾了目前关于ADAR蛋白家族A-to-I编辑的流行和功能的知识，重点是它在基因表达调控中的作用。 此外，还将讨论ADAR对细胞过程的RNA编辑独立调控，以及这一过程在基因调控中的可能作用。
ADAR: A--I(N--O,氨基换成酮基) The extent and role of adenosine to inosine (A-to-I) RNA editing has only recently come to light with the advent of RNA-sequencing technologies. Given that inosine preferentially base pairs with cytosine, A-to-I editing has the potential to drastically alter the coding and structural properties of RNA. The first observation of RNA editing came from the characterization of an activity in Xenopus embryos causing differential migration of RNA:RNA duplexes on a gel [1]. Although this was thought to be a result of duplex unwinding, it was later determined to be caused by the destabilization of RNA duplexes through the C6 deamination of A-to-I by adenosine deaminase acting on the double-stranded RNA (ADAR) [2]. ADAR was later cloned in mammalian cells [3]. The ADAR family is highly conserved across metazoans, with the presence of ADAR members in the earliest-branching metazoan taxa, including sponges and ctenophores [4]. Humans have three ADAR genes (Fig. 1): ADAR1, ADAR2 (also known as ADARB1 or RED1), and ADAR3 (also known as ADARB2 or RED2). ADAR1 has two major isoforms: an interferon inducible ADAR1 p150 that contains both the Za and Zb Z-DNA-binding domains, and a constitutive ADAR1 p110 that lacks the N-terminal Za ZDNA-binding domain [5,6], while ADAR2 lacks any Z-DNA-binding domains [7]. The Zb domain lacks several conserved residues necessary for Z-DNA binding [8,9]. Consequently, only the Za domain has been shown to be able to bind Z-DNA [8], although its function is still unclear and debated. Although ADAR3 has not been shown to possess any catalytic activity, it is able to bind to both single (ssRNA) and double-stranded RNA (dsRNA) [7]. The signifi- cance of ADAR3 binding to ssRNA through its arginine-rich R-domain is unknown and this activity has only been demonstrated in vitro. The R-domain of ADAR3 has been shown to act as a nuclear localization sequence by interacting with importin subunit alpha-1 (KPNA2) [10]. The function of ADAR3 is still being explored, although evidence suggests that it may negatively regulate A-to-I editing in the brain and effect transcriptomic plasticity [7,11]. In Caenorhabditis elegans, the catalytically inactive ADA-1 was found to regulate RNA editing by the catalytically active ADA-2 [12], although it is unclear if a similar mechanism exists in humans. Both ADAR1 and ADAR2 are essential for normal growth and development. Loss of ADAR1 is embryonically lethal in mice by embryonic day E12.5 [12] due to impaired hematopoiesis and the development of severe type-I interferonopathy [13]. ADAR1-deficient hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) show abolished capacity to repopulate an irradiated recipient, suggesting that ADAR1 has a role in both the differentiation and survival of these cells [14]. Furthermore, ADAR1 is essential for HSC and HPC maintenance in the fetal liver and bone marrow [13] and induced expression of a catalytically dead mutant of ADAR in HSCs results in mice developing severe hematopoietic defects [15]. Embryonic lethality of ADAR1 knockout mice can be rescued by subsequent deletion of MAVS [16], a protein that induces type-I interferon and NF-jB signaling, or the upstream effector MDA5 (also known as IFIH1) [17,18] that is involved in the viral defense pathway by acting as a sensor for dsRNA [19]. This points to the role of ADAR editing in negatively regulating the MAVS-MDA5 pathway and preventing activation of an immune response by endogenous transcripts by destabilizing host-derived dsRNA structures. This destabilization prevents MDA5 from forming filaments and triggering an immune response as MDA5 is sensitive to bulges and mismatches in dsRNA [20] (see Ref. [21] for a more detailed overview). ADAR1 is also able to inhibit RIG-I activation by endogenous dsRNAs by directly competing with its binding for the substrate [22]. Both the editing and binding activities of ADAR are necessary to first of all suppress endogenous interferon responses and further prevent translational shutdown during such a response [23]. Mice harboring a genetic knockout of ADAR2 are born at normal mendelian ratios, suggesting that ADAR2 is dispensable for embryological development [24]. However, postnatal lethality is observed in ADAR2 null mice due to progressively worse brain seizures which result in death within 3 weeks of birth [24]. Both ADAR1 and ADAR2 have been reported to form homodimers and heterodimers with each other [25] presenting the possibility of multiple regulatory mechanisms controlling editing Recently, the editing and stability of CTN-RNA was found to be dependent upon the interaction between ADAR1 and ADAR2 in cells [26], suggesting that editing of select RNA substrates is dependent upon the cooperativity between these two ADAR members. It is, however, unclear if this editing occurs through the heterodimerization of ADAR1 and ADAR2, or rather whether binding and editing of CTN-RNA by one ADAR isoform promotes the binding and editing activity of the other. Discrepancy between in vitro and in vivo heterodimerization data may suggest that post-translational modi- fications or other protein-binding partners may be required to facilitate this interaction. The expression of ADAR3, however, is restricted to certain brain regions and postmitotic neurons [7,27].
参考文献：Shevchenko Galina,Morris Kevin V,All I's on the RADAR: role of ADAR in gene regulation.[J] .FEBS Lett, 2018, 592: 2860-2873. |
|
|
