TOE1 acts as a 3' exonuclease for telomerase RNA and regulates telomere maintenance.
TOE1 acts as a 3' exonuclease for telomerase RNA and regulates telomere maintenance.
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TOE1 充当端粒酶 RNA 的 3' 核酸外切酶并调节端粒维持。
DOI：
10.1093/nar/gky1019
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发表时间：
2019-01-10
影响因子：
14.9
通讯作者：
Songyang Z
中科院分区：
文献类型：
--
作者：
Deng T;Huang Y;Weng K;Lin S;Li Y;Shi G;Chen Y;Huang J;Liu D;Ma W;Songyang Z
在人类细胞中，端粒被含有逆转录酶hTERT和RNA模板TERC/hTR的端粒酶复合物延长。已知聚（A）特异性核糖核酸酶（PARN）通过去除聚（A）尾来修剪hTR前体。然而，hTR 3′成熟的确切机制仍不清楚。Egr 1（TOE 1）的靶标是一个Asp-Glu-Asp-Asp（DEDD）结构域，含有在人类疾病脑桥小脑发育不全7型（PCH 7）中突变的脱腺苷酶，并参与snRNA和hTR加工。我们以前发现TOE 1定位于Cajal体，端粒酶RNP复合物组装发生。在这项研究中，我们发现TOE 1可以与hTR和端粒酶复合物相互作用。TOE 1缺陷细胞积累hTR前体，包括寡腺苷酸化和3′-延伸形式，这伴随着端粒酶活性受损和端粒缩短。TOE 1缺陷细胞中的端粒酶活性可以被野生型TOE 1挽救，但不能被催化失活突变体挽救。我们的研究结果表明，hTR 3′端加工可能涉及多个平行和/或顺序工作的核酸外切酶，其中TOE 1可能作为3′-to-5′核酸外切酶与PARN一起发挥非冗余功能。我们的研究强调了TOE 1突变，hTR加工不当和PCH 7等疾病中端粒功能障碍之间的机制联系。
In human cells, telomeres are elongated by the telomerase complex that contains the reverse transcriptase hTERT and RNA template TERC/hTR. Poly(A)-specific ribonuclease (PARN) is known to trim hTR precursors by removing poly(A) tails. However, the precise mechanism of hTR 3′ maturation remains largely unknown. Target of Egr1 (TOE1) is an Asp-Glu-Asp-Asp (DEDD) domain containing deadenylase that is mutated in the human disease Pontocerebella Hypoplasia Type 7 (PCH7) and implicated in snRNA and hTR processing. We have previously found TOE1 to localize specifically in Cajal bodies, where telomerase RNP complex assembly takes place. In this study, we showed that TOE1 could interact with hTR and the telomerase complex. TOE1-deficient cells accumulated hTR precursors, including oligoadenylated and 3′-extended forms, which was accompanied by impaired telomerase activity and shortened telomeres. Telomerase activity in TOE1-deficient cells could be rescued by wild-type TOE1 but not the catalytically inactive mutant. Our results suggest that hTR 3′ end processing likely involves multiple exonucleases that work in parallel and/or sequentially, where TOE1 may function non-redundantly as a 3′-to-5′ exonuclease in conjunction with PARN. Our study highlights a mechanistic link between TOE1 mutation, improper hTR processing and telomere dysfunction in diseases such as PCH7.
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影响因子：
30.8
作者：
Lardelli RM;Schaffer AE;Eggens VR;Zaki MS;Grainger S;Sathe S;Van Nostrand EL;Schlachetzki Z;Rosti B;Akizu N;Scott E;Silhavy JL;Heckman LD;Rosti RO;Dikoglu E;Gregor A;Guemez-Gamboa A;Musaev D;Mande R;Widjaja A;Shaw TL;Markmiller S;Marin-Valencia I;Davies JH;de Meirleir L;Kayserili H;Altunoglu U;Freckmann ML;Warwick L;Chitayat D;Blaser S;Çağlayan AO;Bilguvar K;Per H;Fagerberg C;Christesen HT;Kibaek M;Aldinger KA;Manchester D;Matsumoto N;Muramatsu K;Saitsu H;Shiina M;Ogata K;Foulds N;Dobyns WB;Chi NC;Traver D;Spaccini L;Bova SM;Gabriel SB;Gunel M;Valente EM;Nassogne MC;Bennett EJ;Yeo GW;Baas F;Lykke-Andersen J;Gleeson JG
通讯作者：
Gleeson JG
影响因子：
4.8
作者：
de Belle, I;Wu, JX;Adamson, ED
通讯作者：
Adamson, ED
DOI：
10.1182/asheducation-2011.1.480
发表时间：
2011-12-01
期刊：
HEMATOLOGY-AMERICAN SOCIETY HEMATOLOGY EDUCATION PROGRAM
影响因子：
--
作者：
Dokal, Inderjeet
通讯作者：
Dokal, Inderjeet
影响因子：
21.3
作者：
Liu, D;Safari, A;Zhou, SY
通讯作者：
Zhou, SY
影响因子：
56.9
作者：
FENG, JL;FUNK, WD;VILLEPONTEAU, B
通讯作者：
VILLEPONTEAU, B