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Structural highlights

Disease

TRIPC_HUMAN Non-specific syndromic intellectual disability. The disease is caused by variants affecting the gene represented in this entry.

Function

TRIPC_HUMAN E3 ubiquitin-protein ligase involved in ubiquitin fusion degradation (UFD) pathway and regulation of DNA repair (PubMed:19028681, PubMed:22884692). Part of the ubiquitin fusion degradation (UFD) pathway, a process that mediates ubiquitination of protein at their N-terminus, regardless of the presence of lysine residues in target proteins (PubMed:19028681). Acts as a key regulator of DNA damage response by acting as a suppressor of RNF168, an E3 ubiquitin-protein ligase that promotes accumulation of 'Lys-63'-linked histone H2A and H2AX at DNA damage sites, thereby acting as a guard against excessive spreading of ubiquitinated chromatin at damaged chromosomes (PubMed:22884692). In normal cells, mediates ubiquitination and degradation of isoform p19ARF/ARF of CDKN2A, a lysine-less tumor suppressor required for p53/TP53 activation under oncogenic stress (PubMed:20208519). In cancer cells, however, isoform p19ARF/ARF and TRIP12 are located in different cell compartments, preventing isoform p19ARF/ARF ubiquitination and degradation (PubMed:20208519). Does not mediate ubiquitination of isoform p16-INK4a of CDKN2A (PubMed:20208519). Also catalyzes ubiquitination of NAE1 and SMARCE1, leading to their degradation (PubMed:18627766). Ubiquitination and degradation of target proteins is regulated by interaction with proteins such as MYC, TRADD or SMARCC1, which disrupt the interaction between TRIP12 and target proteins (PubMed:20829358). Mediates ubiquitination of ASXL1: following binding to N(6)-methyladenosine methylated DNA, ASXL1 is ubiquitinated by TRIP12, leading to its degradation and subsequent inactivation of the PR-DUB complex (PubMed:30982744).^{[1] [2] [3] [4] [5] [6]}

References

1. ↑ Park Y, Yoon SK, Yoon JB. TRIP12 functions as an E3 ubiquitin ligase of APP-BP1. Biochem Biophys Res Commun. 2008 Sep 19;374(2):294-8. PMID:18627766 doi:10.1016/j.bbrc.2008.07.019
2. ↑ Park Y, Yoon SK, Yoon JB. The HECT domain of TRIP12 ubiquitinates substrates of the ubiquitin fusion degradation pathway. J Biol Chem. 2009 Jan 16;284(3):1540-9. PMID:19028681 doi:10.1074/jbc.M807554200
3. ↑ Chen D, Shan J, Zhu WG, Qin J, Gu W. Transcription-independent ARF regulation in oncogenic stress-mediated p53 responses. Nature. 2010 Mar 25;464(7288):624-7. PMID:20208519 doi:10.1038/nature08820
4. ↑ Keppler BR, Archer TK. Ubiquitin-dependent and ubiquitin-independent control of subunit stoichiometry in the SWI/SNF complex. J Biol Chem. 2010 Nov 12;285(46):35665-74. PMID:20829358 doi:10.1074/jbc.M110.173997
5. ↑ Gudjonsson T, Altmeyer M, Savic V, Toledo L, Dinant C, Grofte M, Bartkova J, Poulsen M, Oka Y, Bekker-Jensen S, Mailand N, Neumann B, Heriche JK, Shearer R, Saunders D, Bartek J, Lukas J, Lukas C. TRIP12 and UBR5 suppress spreading of chromatin ubiquitylation at damaged chromosomes. Cell. 2012 Aug 17;150(4):697-709. doi: 10.1016/j.cell.2012.06.039. Epub 2012 Aug , 9. PMID:22884692 doi:http://dx.doi.org/10.1016/j.cell.2012.06.039
6. ↑ Kweon SM, Chen Y, Moon E, Kvederaviciutė K, Klimasauskas S, Feldman DE. An Adversarial DNA N(6)-Methyladenine-Sensor Network Preserves Polycomb Silencing. Mol Cell. 2019 Jun 20;74(6):1138-1147.e6. PMID:30982744 doi:10.1016/j.molcel.2019.03.018