| Structural highlights
Function
[TASOR_HUMAN] Component of the HUSH complex, a multiprotein complex that mediates epigenetic repression (PubMed:26022416, PubMed:28581500). The HUSH complex is recruited to genomic loci rich in H3K9me3 and is required to maintain transcriptional silencing by promoting recruitment of SETDB1, a histone methyltransferase that mediates further deposition of H3K9me3, as well as MORC2 (PubMed:26022416, PubMed:28581500). Also represses L1 retrotransposons in collaboration with MORC2 and, probably, SETDB1, the silencing is dependent of repressive epigenetic modifications, such as H3K9me3 mark. Silencing events often occur within introns of transcriptionally active genes, and lead to the down-regulation of host gene expression (PubMed:29211708). The HUSH complex is also involved in the silencing of unintegrated retroviral DNA by being recruited by ZNF638: some part of the retroviral DNA formed immediately after infection remains unintegrated in the host genome and is transcriptionally repressed (PubMed:30487602). Plays a crucial role in early embryonic development (By similarity). Involved in the organization of spindle poles and spindle apparatus assembly during zygotic division (By similarity). Plays an important role in maintaining epiblast fitness or potency (By similarity).[UniProtKB:Q69ZR9][1] [2] [3] [4]
Publication Abstract from PubMed
The HUSH complex represses retroviruses, transposons and genes to maintain the integrity of vertebrate genomes. HUSH regulates deposition of the epigenetic mark H3K9me3, but how its three core subunits - TASOR, MPP8 and Periphilin - contribute to assembly and targeting of the complex remains unknown. Here, we define the biochemical basis of HUSH assembly and find that its modular architecture resembles the yeast RNA-induced transcriptional silencing complex. TASOR, the central HUSH subunit, associates with RNA processing components. TASOR is required for H3K9me3 deposition over LINE-1 repeats and repetitive exons in transcribed genes. In the context of previous studies, this suggests that an RNA intermediate is important for HUSH activity. We dissect the TASOR and MPP8 domains necessary for transgene repression. Structure-function analyses reveal TASOR bears a catalytically-inactive PARP domain necessary for targeted H3K9me3 deposition. We conclude that TASOR is a multifunctional pseudo-PARP that directs HUSH assembly and epigenetic regulation of repetitive genomic targets.
TASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control.,Douse CH, Tchasovnikarova IA, Timms RT, Protasio AV, Seczynska M, Prigozhin DM, Albecka A, Wagstaff J, Williamson JC, Freund SMV, Lehner PJ, Modis Y Nat Commun. 2020 Oct 2;11(1):4940. doi: 10.1038/s41467-020-18761-6. PMID:33009411[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Tchasovnikarova IA, Timms RT, Matheson NJ, Wals K, Antrobus R, Gottgens B, Dougan G, Dawson MA, Lehner PJ. GENE SILENCING. Epigenetic silencing by the HUSH complex mediates position-effect variegation in human cells. Science. 2015 Jun 26;348(6242):1481-1485. doi: 10.1126/science.aaa7227. Epub 2015, May 28. PMID:26022416 doi:http://dx.doi.org/10.1126/science.aaa7227
- ↑ Tchasovnikarova IA, Timms RT, Douse CH, Roberts RC, Dougan G, Kingston RE, Modis Y, Lehner PJ. Hyperactivation of HUSH complex function by Charcot-Marie-Tooth disease mutation in MORC2. Nat Genet. 2017 Jul;49(7):1035-1044. doi: 10.1038/ng.3878. Epub 2017 Jun 5. PMID:28581500 doi:http://dx.doi.org/10.1038/ng.3878
- ↑ Liu N, Lee CH, Swigut T, Grow E, Gu B, Bassik MC, Wysocka J. Selective silencing of euchromatic L1s revealed by genome-wide screens for L1 regulators. Nature. 2018 Jan 11;553(7687):228-232. doi: 10.1038/nature25179. Epub 2017 Dec 6. PMID:29211708 doi:http://dx.doi.org/10.1038/nature25179
- ↑ Zhu Y, Wang GZ, Cingoz O, Goff SP. NP220 mediates silencing of unintegrated retroviral DNA. Nature. 2018 Dec;564(7735):278-282. doi: 10.1038/s41586-018-0750-6. Epub 2018 Nov, 28. PMID:30487602 doi:http://dx.doi.org/10.1038/s41586-018-0750-6
- ↑ Douse CH, Tchasovnikarova IA, Timms RT, Protasio AV, Seczynska M, Prigozhin DM, Albecka A, Wagstaff J, Williamson JC, Freund SMV, Lehner PJ, Modis Y. TASOR is a pseudo-PARP that directs HUSH complex assembly and epigenetic transposon control. Nat Commun. 2020 Oct 2;11(1):4940. doi: 10.1038/s41467-020-18761-6. PMID:33009411 doi:http://dx.doi.org/10.1038/s41467-020-18761-6
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