Pre-mRNA-processing factor 19

Definition:

Ubiquitin-protein ligase which is a core component of several complexes mainly involved pre-mRNA splicing and DNA repair. Required for pre-mRNA splicing as component of the spliceosome. Core component of the PRP19C/Prp19 complex/NTC/Nineteen complex which is part of the spliceosome and participates in its assembly, its remodeling and is required for its activity. During assembly of the spliceosome, mediates 'Lys-63'-linked polyubiquitination of the U4 spliceosomal protein PRPF3. Ubiquitination of PRPF3 allows its recognition by the U5 component PRPF8 and stabilizes the U4/U5/U6 tri-snRNP spliceosomal complex. Recruited to RNA polymerase II C-terminal domain (CTD) and the pre-mRNA, it may also couple the transcriptional and spliceosomal machineries. The XAB2 complex, which contains PRPF19, is also involved in pre-mRNA splicing, transcription and transcription-coupled repair. Beside its role in pre-mRNA splicing PRPF19, as part of the PRP19-CDC5L complex, plays a role in the DNA damage response/DDR. It is recruited to the sites of DNA damage by the RPA complex where PRPF19 directly ubiquitinates RPA1 and RPA2. 'Lys-63'-linked polyubiquitination of the RPA complex allows the recruitment of the ATR-ATRIP complex and the activation of ATR, a master regulator of the DNA damage response. May also play a role in DNA double-strand break (DSB) repair by recruiting the repair factor SETMAR to altered DNA. As part of the PSO4 complex may also be involved in the DNA interstrand cross-links/ICLs repair process. In addition, may also mediate 'Lys-48'-linked polyubiquitination of substrates and play a role in proteasomal degradation. May play a role in the biogenesis of lipid droplets (By similarity). May play a role in neural differentiation possibly through its function as part of the spliceosome (By similarity).

References:

[1]. Xiaofeng Zhang, et al. An Atomic Structure of the Human Spliceosome. Cell. 2017 May 18;169(5):918-929.e14. [Content Brief]

[2]. Xiechao Zhan, et al. Structure of a human catalytic step I spliceosome. Science. 2018 Feb 2;359(6375):537-545. [Content Brief]

[3]. S Hatakeyama, et al. U box proteins as a new family of ubiquitin-protein ligases. J Biol Chem. 2001 Aug 31;276(35):33111-20. [Content Brief]

[4]. Regina Voglauer, et al. SNEV overexpression extends the life span of human endothelial cells. Exp Cell Res. 2006 Apr 1;312(6):746-59. [Content Brief]

[5]. Xiaofeng Zhang, et al. Structure of the human activated spliceosome in three conformational states. Cell Res. 2018 Mar;28(3):307-322. [Content Brief]

[6]. Karl Bertram, et al. Cryo-EM structure of a human spliceosome activated for step 2 of splicing. Nature. 2017 Feb 16;542(7641):318-323. [Content Brief]

[7]. Marlies Löscher, et al. Interaction of U-box E3 ligase SNEV with PSMB4, the beta7 subunit of the 20 S proteasome. Biochem J. 2005 Jun 1;388(Pt 2):593-603. [Content Brief]

[8]. Brian D Beck, et al. Human Pso4 is a metnase (SETMAR)-binding partner that regulates metnase function in DNA repair. J Biol Chem. 2008 Apr 4;283(14):9023-30. [Content Brief]

[9]. J Gotzmann, et al. hNMP 200: a novel human common nuclear matrix protein combining structural and regulatory functions. Exp Cell Res. 2000 Nov 25;261(1):166-79. [Content Brief]

[10]. Isao Kuraoka, et al. Isolation of XAB2 complex involved in pre-mRNA splicing, transcription, and transcription-coupled repair. J Biol Chem. 2008 Jan 11;283(2):940-50. [Content Brief]

[11]. Sebastian M Fica, et al. A human postcatalytic spliceosome structure reveals essential roles of metazoan factors for exon ligation. Science. 2019 Feb 15;363(6428):710-714. [Content Brief]

[12]. Eun Joo Song, et al. The Prp19 complex and the Usp4Sart3 deubiquitinating enzyme control reversible ubiquitination at the spliceosome. Genes Dev. 2010 Jul 1;24(13):1434-47. [Content Brief]

[13]. Charles J David, et al. The RNA polymerase II C-terminal domain promotes splicing activation through recruitment of a U2AF65-Prp19 complex. Genes Dev. 2011 May 1;25(9):972-83. [Content Brief]

[14]. Nianxiang Zhang, et al. The Pso4 mRNA splicing and DNA repair complex interacts with WRN for processing of DNA interstrand cross-links. J Biol Chem. 2005 Dec 9;280(49):40559-67. [Content Brief]

[15]. Choong-Ryoul Sihn, et al. Mouse homologue of yeast Prp19 interacts with mouse SUG1, the regulatory subunit of 26S proteasome. Biochem Biophys Res Commun. 2007 Apr 27;356(1):175-80. [Content Brief]

[16]. Kiran N Mahajan, et al. Role of human Pso4 in mammalian DNA repair and association with terminal deoxynucleotidyl transferase. Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10746-51. [Content Brief]

[17]. Johannes Grillari, et al. SNEV is an evolutionarily conserved splicing factor whose oligomerization is necessary for spliceosome assembly. Nucleic Acids Res. 2005 Dec 6;33(21):6868-83. [Content Brief]

[18]. Alexandre Maréchal, et al. PRP19 transforms into a sensor of RPA-ssDNA after DNA damage and drives ATR activation via a ubiquitin-mediated circuitry. Mol Cell. 2014 Jan 23;53(2):235-246. [Content Brief]

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