TAR DNA-binding protein 43

Definition:

RNA-binding protein that is involved in various steps of RNA biogenesis and processing. Preferentially binds, via its two RNA recognition motifs RRM1 and RRM2, to GU-repeats on RNA molecules predominantly localized within long introns and in the 3'UTR of mRNAs. In turn, regulates the splicing of many non-coding and protein-coding RNAs including proteins involved in neuronal survival, as well as mRNAs that encode proteins relevant for neurodegenerative diseases. Plays a role in maintaining mitochondrial homeostasis by regulating the processing of mitochondrial transcripts. Regulates also mRNA stability by recruiting CNOT7/CAF1 deadenylase on mRNA 3'UTR leading to poly(A) tail deadenylation and thus shortening. In response to oxidative insult, associates with stalled ribosomes localized to stress granules (SGs) and contributes to cell survival. Participates also in the normal skeletal muscle formation and regeneration, forming cytoplasmic myo-granules and binding mRNAs that encode sarcomeric proteins. Plays a role in the maintenance of the circadian clock periodicity via stabilization of the CRY1 and CRY2 proteins in a FBXL3-dependent manner. Negatively regulates the expression of CDK6. Regulates the expression of HDAC6, ATG7 and VCP in a PPIA/CYPA-dependent manner.

References:

[1]. Amit Bhardwaj, et al. Characterizing TDP-43 interaction with its RNA targets. Nucleic Acids Res. 2013 May;41(9):5062-74. [Content Brief]

[2]. Thomas O Vogler, et al. TDP-43 and RNA form amyloid-like myo-granules in regenerating muscle. Nature. 2018 Nov;563(7732):508-513. [Content Brief]

[3]. Keiichi Izumikawa, et al. TDP-43 stabilises the processing intermediates of mitochondrial transcripts. Sci Rep. 2017 Aug 9;7(1):7709. [Content Brief]

[4]. Claudia Colombrita, et al. TDP-43 is recruited to stress granules in conditions of oxidative insult. J Neurochem. 2009 Nov;111(4):1051-61. [Content Brief]

[5]. E Buratti, et al. Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping. EMBO J. 2001 Apr 2;20(7):1774-84. [Content Brief]

[6]. Makoto Fukushima, et al. TDP-43 accelerates deadenylation of target mRNAs by recruiting Caf1 deadenylase. FEBS Lett. 2019 Feb;593(3):277-287. [Content Brief]

[7]. James R Tollervey, et al. Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci. 2011 Apr;14(4):452-8. [Content Brief]

[8]. Michael J Strong, et al. TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Mol Cell Neurosci. 2007 Jun;35(2):320-7. [Content Brief]

[9]. Peter J Lukavsky, et al. Molecular basis of UG-rich RNA recognition by the human splicing factor TDP-43. Nat Struct Mol Biol. 2013 Dec;20(12):1443-9. [Content Brief]

[10]. Ailin Wang, et al. A single N-terminal phosphomimic disrupts TDP-43 polymerization, phase separation, and RNA splicing. EMBO J. 2018 Mar 1;37(5):e97452. [Content Brief]

[11]. Shinji Higashi, et al. TDP-43 associates with stalled ribosomes and contributes to cell survival during cellular stress. J Neurochem. 2013 Jul;126(2):288-300. [Content Brief]

[12]. Eliana Lauranzano, et al. Peptidylprolyl isomerase A governs TARDBP function and assembly in heterogeneous nuclear ribonucleoprotein complexes. Brain. 2015 Apr;138(Pt 4):974-91. [Content Brief]

[13]. Janine Kirby, et al. Broad clinical phenotypes associated with TAR-DNA binding protein (TARDBP) mutations in amyotrophic lateral sclerosis. Neurogenetics. 2010 May;11(2):217-25. [Content Brief]

[14]. Pan-Hsien Kuo, et al. The crystal structure of TDP-43 RRM1-DNA complex reveals the specific recognition for UG- and TG-rich nucleic acids. Nucleic Acids Res. 2014 Apr;42(7):4712-22. [Content Brief]

[15]. Arisa Hirano, et al. USP7 and TDP-43: Pleiotropic Regulation of Cryptochrome Protein Stability Paces the Oscillation of the Mammalian Circadian Clock. PLoS One. 2016 Apr 28;11(4):e0154263. [Content Brief]

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