DNA topoisomerase 2-associated proteins PATL1 and PATL2 regulate the biogenesis of hERG K(+) channels.
DNA topoisomerase 2-associated proteins PATL1 and PATL2 regulate the biogenesis of hERG K(+) channels.
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DOI：
10.1073/pnas.2206146120
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发表时间：
2023-01-10
影响因子：
11.1
通讯作者：
中科院分区：
文献类型：
--
作者：
Precise regulation of hERG channel biogenesis is critical for maintaining normal physiological functions of the channel. Misregulation of this process results in human diseases, such as long QT syndrome. Here, we identified two DNA topoisomerase 2-associated proteins PATL1 and PATL2 as novel regulators for the biogenesis of hERG channels at the transcriptional level. Classically, DNA topoisomerase 2-related proteins are known to participate in mRNA degradation and translation inhibition. Here, we found that PATL1 and PATL2 facilitate the transcription of hERG channels by interacting with the transcription factor TFIIE, revealing a novel mechanism underlying the biogenesis of hERG channels. The human ether-a-go-go-related gene (hERG) K+ channel conducts a rapidly activating delayed rectifier K+ current (IKr), which is essential for normal electrical activity of the heart. Precise regulation of hERG channel biogenesis is critical for serving its physiological functions, and deviations from the regulation result in human diseases. However, the mechanism underlying the precise regulation of hERG channel biogenesis remains elusive. Here, by using forward genetic screen, we found that PATR-1, the Caenorhabditis elegans homolog of the yeast DNA topoisomerase 2-associated protein PAT1, is a critical regulator for the biogenesis of UNC-103, the ERG K+ channel in C. elegans. A loss-of-function mutation in patr-1 down-regulates the expression level of UNC-103 proteins and suppresses the phenotypic defects resulted from a gain-of-function mutation in the unc-103 gene. Furthermore, downregulation of PATL1 and PATL2, the human homologs of PAT1, decreases protein levels and the current density of native hERG channels in SH-SY5Y cells and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Knockdown of PATL1 and PATL2 elongates the duration of action potentials in hiPSC-CMs, suggesting that PATL1 and PATL2 affect the function of hERG channels and hence electrophysiological characteristics in the human heart. Further studies found that PATL1 and PATL2 interact with TFIIE, a general transcription factor required for forming the RNA polymerase II preinitiation complex, and dual-luciferase reporter assays indicated that PATL1 and PATL2 facilitate the transcription of hERG mRNAs. Together, our study discovers that evolutionarily conserved DNA topoisomerase 2-associated proteins regulate the biogenesis of hERG channels via a transcriptional mechanism.
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影响因子：
16
作者：
Anindya, Roy;Ayguen, Ozan;Svejstrup, Jesper Q.
通讯作者：
Svejstrup, Jesper Q.
影响因子：
11.4
作者：
Braun, Joerg E.;Tritschler, Felix;Haas, Gabrielle;Igreja, Catia;Truffault, Vincent;Weichenrieder, Oliver;Izaurralde, Elisa
通讯作者：
Izaurralde, Elisa
影响因子：
3.3
作者：
Apaja PM;Foo B;Okiyoneda T;Valinsky WC;Barriere H;Atanasiu R;Ficker E;Lukacs GL;Shrier A
通讯作者：
Shrier A
影响因子：
64.5
作者：
Koelle, MR;Horvitz, HR
通讯作者：
Horvitz, HR
使用代谢标签4-硫岛碱分离新转录的RNA。
DOI：
10.1007/978-1-4939-7204-3_13
发表时间：
2017
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Garibaldi A;Carranza F;Hertel KJ
通讯作者：
Hertel KJ