Iron availability modulates aberrant splicing of ferrochelatase through the iron- and 2-oxoglutarate dependent dioxygenase Jmjd6 and U2AF65
Iron availability modulates aberrant splicing of ferrochelatase through the iron- and 2-oxoglutarate dependent dioxygenase Jmjd6 and U2AF65
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DOI：
10.1016/j.bcmd.2013.05.008
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发表时间：
2013-10-01
影响因子：
2.3
通讯作者：
Minder, Elisabeth I.
中科院分区：
文献类型：
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作者：
Barman-Aksoezen, Jasmin;Beguin, Chantal;Minder, Elisabeth I.
红细胞生成性原卟啉症（EPP）是由于铁螯合酶（FECH）的部分缺乏引起的。在遗传学上，EPP患者与无症状突变携带者在未突变的FECH等位基因上不同，其表达受单核苷酸多态性IVS 3 - 48 C/T调节。IVS 3 - 48 C基因型存在于患者中，导致60%的前体mRNA的正确剪接和40%的选择性剪接，后者mRNA产物被无义介导的衰变破坏。IVS 3 - 48 T基因型产生80%正确和20%异常产物。我们的研究表明，在缺铁条件下，异常剪接产物增加到56%和50%的总FECH mRNA在红白血病K562和淋巴母细胞系，分别为IVS 3 - 48 T纯合子。同时，FECH蛋白减少。铁缺乏对IVS 3 - 48 C/C淋巴母细胞系中FECH剪接率的影响较小。通过siRNA敲低剪接因子U2 AF（65）或Fe（II）-和2-酮戊二酸依赖性双加氧酶Jumonji结构域蛋白6（Jmjd 6）产生类似于铁缺乏的效应，Jmjd 6通过赖氨酰羟基化与U2 AF 65相互作用。基于这些结果，我们提出铁的可用性，Jmjd 6的辅因子，调节U2 AF（65）-赖氨酰-羟基化。这反过来又影响正确和异常FECH mRNA剪接产物的相对量，从而调节FECH酶活性。(C)2013 Elsevier Inc. All rights reserved.
Erythropoietic protoporphyria (EPP) results from partial deficiency of ferrochelatase (FECH). Genetically, EPP patients differ from asymptomatic mutation carriers at the unmutated FECH allele, the expression of which is modulated by single nucleotide polymorphism IVS3-48C/T. The IVS3-48C genotype, which is present among patients, leads to correct splicing of 60% of the pre-mRNA and to alternative splicing of 40%, the latter mRNA-product being destroyed by nonsense-mediated decay. An IVS3-48T genotype generates 80% correct and 20% aberrant products. Our study demonstrated that under iron deficient conditions, the aberrant splice product was increased to 56% and 50% of total FECH mRNA in erythroleukemic K562 and lymphoblastoid cell lines, respectively, both being homozygous for IVS3-48T. Concomitantly, FECH protein was decreased. Iron deficiency had less effect on the FECH splice ratio in an IVS3-48C/C lymphoblastoid cell line. Effects similar to iron deficiency were generated by siRNA knockdown of either splicing factor U2AF(65) or Fe(II)- and 2-oxoglutarate-dependent dioxygenase Jumonji domain-containing protein 6 (Jmjd6), which interacts with U2AF65 by lysyl-hydroxylation. Based on these results, we propose that the availability of iron, a co-factor of Jmjd6, modulates U2AF(65)-lysyl-hydroxylation. This in turn, influences the relative amounts of correct and aberrant FECH mRNA splice products and thus, regulates the FECH enzyme activity. (C) 2013 Elsevier Inc. All rights reserved.