| Structural highlights
Function
[TIF1B_HUMAN] Nuclear corepressor for KRAB domain-containing zinc finger proteins (KRAB-ZFPs). Mediates gene silencing by recruiting CHD3, a subunit of the nucleosome remodeling and deacetylation (NuRD) complex, and SETDB1 (which specifically methylates histone H3 at 'Lys-9' (H3K9me)) to the promoter regions of KRAB target genes. Enhances transcriptional repression by coordinating the increase in H3K9me, the decrease in histone H3 'Lys-9 and 'Lys-14' acetylation (H3K9ac and H3K14ac, respectively) and the disposition of HP1 proteins to silence gene expression. Recruitment of SETDB1 induces heterochromatinization. May play a role as a coactivator for CEBPB and NR3C1 in the transcriptional activation of ORM1. Also corepressor for ERBB4. Inhibits E2F1 activity by stimulating E2F1-HDAC1 complex formation and inhibiting E2F1 acetylation. May serve as a partial backup to prevent E2F1-mediated apoptosis in the absence of RB1. Important regulator of CDKN1A/p21(CIP1). Has E3 SUMO-protein ligase activity toward itself via its PHD-type zinc finger. Also specifically sumoylates IRF7, thereby inhibiting its transactivation activity. Ubiquitinates p53/TP53 leading to its proteosomal degradation; the function is enhanced by MAGEC2 and MAGEA2, and possibly MAGEA3 and MAGEA6.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17]
Publication Abstract from PubMed
TRIM E3 ubiquitin ligases regulate multiple cellular processes, and their dysfunction is linked to disease. They are characterised by a conserved N-terminal tripartite motif comprising a RING, B-box domains, and a coiled-coil region, with C-terminal domains often mediating substrate recruitment. TRIM proteins are grouped into 11 classes based on C-terminal domain identity. Class VI TRIMs, TRIM24, TRIM33, and TRIM28, have been described as transcriptional regulators, a function linked to their C-terminal plant homeodomain and bromodomain, and independent of their ubiquitination activity. It is unclear whether E3 ligase activity is regulated in family members where the C-terminal domains function independently. Here, we provide a detailed biochemical characterisation of the RING domains of class VI TRIMs and describe the solution structure of the TRIM28 RING. Our study reveals a lack of activity of the isolated RING domains, which may be linked to the absence of self-association. We propose that class VI TRIMs exist in an inactive state and require additional regulatory events to stimulate E3 ligase activity, ensuring that associated chromatin-remodelling factors are not injudiciously degraded.
Characterisation of class VI TRIM RING domains: linking RING activity to C-terminal domain identity.,Stevens RV, Esposito D, Rittinger K Life Sci Alliance. 2019 Apr 26;2(3). pii: 2/3/e201900295. doi:, 10.26508/lsa.201900295. Print 2019 Jun. PMID:31028095[18]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
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- ↑ Moosmann P, Georgiev O, Le Douarin B, Bourquin JP, Schaffner W. Transcriptional repression by RING finger protein TIF1 beta that interacts with the KRAB repressor domain of KOX1. Nucleic Acids Res. 1996 Dec 15;24(24):4859-67. PMID:9016654
- ↑ Agata Y, Matsuda E, Shimizu A. Two novel Kruppel-associated box-containing zinc-finger proteins, KRAZ1 and KRAZ2, repress transcription through functional interaction with the corepressor KAP-1 (TIF1beta/KRIP-1). J Biol Chem. 1999 Jun 4;274(23):16412-22. PMID:10347202
- ↑ Schultz DC, Ayyanathan K, Negorev D, Maul GG, Rauscher FJ 3rd. SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes Dev. 2002 Apr 15;16(8):919-32. PMID:11959841 doi:http://dx.doi.org/10.1101/gad.973302
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- ↑ White DE, Negorev D, Peng H, Ivanov AV, Maul GG, Rauscher FJ 3rd. KAP1, a novel substrate for PIKK family members, colocalizes with numerous damage response factors at DNA lesions. Cancer Res. 2006 Dec 15;66(24):11594-9. PMID:17178852 doi:http://dx.doi.org/10.1158/0008-5472.CAN-06-4138
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- ↑ Lee YK, Thomas SN, Yang AJ, Ann DK. Doxorubicin down-regulates Kruppel-associated box domain-associated protein 1 sumoylation that relieves its transcription repression on p21WAF1/CIP1 in breast cancer MCF-7 cells. J Biol Chem. 2007 Jan 19;282(3):1595-606. Epub 2006 Nov 1. PMID:17079232 doi:http://dx.doi.org/10.1074/jbc.M606306200
- ↑ Wang C, Rauscher FJ 3rd, Cress WD, Chen J. Regulation of E2F1 function by the nuclear corepressor KAP1. J Biol Chem. 2007 Oct 12;282(41):29902-9. Epub 2007 Aug 17. PMID:17704056 doi:10.1074/jbc.M704757200
- ↑ Li X, Lee YK, Jeng JC, Yen Y, Schultz DC, Shih HM, Ann DK. Role for KAP1 serine 824 phosphorylation and sumoylation/desumoylation switch in regulating KAP1-mediated transcriptional repression. J Biol Chem. 2007 Dec 14;282(50):36177-89. Epub 2007 Oct 17. PMID:17942393 doi:http://dx.doi.org/10.1074/jbc.M706912200
- ↑ Ivanov AV, Peng H, Yurchenko V, Yap KL, Negorev DG, Schultz DC, Psulkowski E, Fredericks WJ, White DE, Maul GG, Sadofsky MJ, Zhou MM, Rauscher FJ 3rd. PHD domain-mediated E3 ligase activity directs intramolecular sumoylation of an adjacent bromodomain required for gene silencing. Mol Cell. 2007 Dec 14;28(5):823-37. PMID:18082607 doi:http://dx.doi.org/10.1016/j.molcel.2007.11.012
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- ↑ Gilmore-Hebert M, Ramabhadran R, Stern DF. Interactions of ErbB4 and Kap1 connect the growth factor and DNA damage response pathways. Mol Cancer Res. 2010 Oct;8(10):1388-98. doi: 10.1158/1541-7786.MCR-10-0042. Epub , 2010 Sep 21. PMID:20858735 doi:10.1158/1541-7786.MCR-10-0042
- ↑ Doyle JM, Gao J, Wang J, Yang M, Potts PR. MAGE-RING protein complexes comprise a family of E3 ubiquitin ligases. Mol Cell. 2010 Sep 24;39(6):963-74. PMID:20864041 doi:10.1016/j.molcel.2010.08.029
- ↑ Li X, Lin HH, Chen H, Xu X, Shih HM, Ann DK. SUMOylation of the transcriptional co-repressor KAP1 is regulated by the serine and threonine phosphatase PP1. Sci Signal. 2010 Apr 27;3(119):ra32. doi: 10.1126/scisignal.2000781. PMID:20424263 doi:http://dx.doi.org/10.1126/scisignal.2000781
- ↑ Liang Q, Deng H, Li X, Wu X, Tang Q, Chang TH, Peng H, Rauscher FJ 3rd, Ozato K, Zhu F. Tripartite motif-containing protein 28 is a small ubiquitin-related modifier E3 ligase and negative regulator of IFN regulatory factor 7. J Immunol. 2011 Nov 1;187(9):4754-63. doi: 10.4049/jimmunol.1101704. Epub 2011, Sep 21. PMID:21940674 doi:http://dx.doi.org/10.4049/jimmunol.1101704
- ↑ Stevens RV, Esposito D, Rittinger K. Characterisation of class VI TRIM RING domains: linking RING activity to C-terminal domain identity. Life Sci Alliance. 2019 Apr 26;2(3). pii: 2/3/e201900295. doi:, 10.26508/lsa.201900295. Print 2019 Jun. PMID:31028095 doi:http://dx.doi.org/10.26508/lsa.201900295
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