| Structural highlights
Function
[SMHD1_MOUSE] Non-canonical member of the structural maintenance of chromosomes (SMC) protein family that plays a key role in epigenetic silencing by regulating chromatin architecture (PubMed:26091879, PubMed:29887375). Promotes heterochromatin formation in both autosomes and chromosome X, probably by mediating the merge of chromatin compartments (PubMed:23754746, PubMed:23819640, PubMed:26391951, PubMed:28587678, PubMed:29887375). Plays a key role in chromosome X inactivation in females by promoting the spreading of heterochromatin (PubMed:18425126, PubMed:22841499, PubMed:26391951, PubMed:29887375). Recruited to inactivated chromosome X by Xist RNA and acts by mediating the merge of chromatin compartments: promotes random chromatin interactions that span the boundaries of existing structures, leading to create a compartment-less architecture typical of inactivated chromosome X (PubMed:29887375). Required to facilitate Xist RNA spreading (PubMed:29887375). Also required for silencing of a subset of clustered autosomal loci in somatic cells, such as the DUX4 locus (PubMed:23754746, PubMed:23819640, PubMed:28587678). Has ATPase activity; may participate in structural manipulation of chromatin in an ATP-dependent manner as part of its role in gene expression regulation (PubMed:26391951, PubMed:27059856). Also plays a role in DNA repair: localizes to sites of DNA double-strand breaks in response to DNA damage to promote the repair of DNA double-strand breaks (By similarity). Acts by promoting non-homologous end joining (NHEJ) and inhibiting homologous recombination (HR) repair (By similarity). Required during preimplantation development, probably acts by regulating chromatin architecture (PubMed:29900695).[UniProtKB:A6NHR9][1] [2] [3] [4] [5] [6] [7] [8] [9] [10]
Publication Abstract from PubMed
Structural maintenance of chromosomes flexible hinge domain containing 1 (SMCHD1) is an epigenetic regulator in which polymorphisms cause the human developmental disorder, Bosma arhinia micropthalmia syndrome, and the degenerative disease, facioscapulohumeral muscular dystrophy. SMCHD1 is considered a noncanonical SMC family member because its hinge domain is C-terminal, because it homodimerizes rather than heterodimerizes, and because SMCHD1 contains a GHKL-type, rather than an ABC-type ATPase domain at its N terminus. The hinge domain has been previously implicated in chromatin association; however, the underlying mechanism involved and the basis for SMCHD1 homodimerization are unclear. Here, we used x-ray crystallography to solve the three-dimensional structure of the Smchd1 hinge domain. Together with structure-guided mutagenesis, we defined structural features of the hinge domain that participated in homodimerization and nucleic acid binding, and we identified a functional hotspot required for chromatin localization in cells. This structure provides a template for interpreting the mechanism by which patient polymorphisms within the SMCHD1 hinge domain could compromise function and lead to facioscapulohumeral muscular dystrophy.
Crystal structure of the hinge domain of Smchd1 reveals its dimerization mode and nucleic acid-binding residues.,Chen K, Birkinshaw RW, Gurzau AD, Wanigasuriya I, Wang R, Iminitoff M, Sandow JJ, Young SN, Hennessy PJ, Willson TA, Heckmann DA, Webb AI, Blewitt ME, Czabotar PE, Murphy JM Sci Signal. 2020 Jun 16;13(636). pii: 13/636/eaaz5599. doi:, 10.1126/scisignal.aaz5599. PMID:32546545[11]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Blewitt ME, Gendrel AV, Pang Z, Sparrow DB, Whitelaw N, Craig JM, Apedaile A, Hilton DJ, Dunwoodie SL, Brockdorff N, Kay GF, Whitelaw E. SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation. Nat Genet. 2008 May;40(5):663-9. doi: 10.1038/ng.142. Epub 2008 Apr 20. PMID:18425126 doi:http://dx.doi.org/10.1038/ng.142
- ↑ Gendrel AV, Apedaile A, Coker H, Termanis A, Zvetkova I, Godwin J, Tang YA, Huntley D, Montana G, Taylor S, Giannoulatou E, Heard E, Stancheva I, Brockdorff N. Smchd1-dependent and -independent pathways determine developmental dynamics of CpG island methylation on the inactive X chromosome. Dev Cell. 2012 Aug 14;23(2):265-79. doi: 10.1016/j.devcel.2012.06.011. Epub 2012 , Jul 26. PMID:22841499 doi:http://dx.doi.org/10.1016/j.devcel.2012.06.011
- ↑ Gendrel AV, Tang YA, Suzuki M, Godwin J, Nesterova TB, Greally JM, Heard E, Brockdorff N. Epigenetic functions of smchd1 repress gene clusters on the inactive X chromosome and on autosomes. Mol Cell Biol. 2013 Aug;33(16):3150-65. doi: 10.1128/MCB.00145-13. Epub 2013 Jun , 10. PMID:23754746 doi:http://dx.doi.org/10.1128/MCB.00145-13
- ↑ Mould AW, Pang Z, Pakusch M, Tonks ID, Stark M, Carrie D, Mukhopadhyay P, Seidel A, Ellis JJ, Deakin J, Wakefield MJ, Krause L, Blewitt ME, Kay GF. Smchd1 regulates a subset of autosomal genes subject to monoallelic expression in addition to being critical for X inactivation. Epigenetics Chromatin. 2013 Jul 2;6(1):19. doi: 10.1186/1756-8935-6-19. PMID:23819640 doi:http://dx.doi.org/10.1186/1756-8935-6-19
- ↑ Chen K, Hu J, Moore DL, Liu R, Kessans SA, Breslin K, Lucet IS, Keniry A, Leong HS, Parish CL, Hilton DJ, Lemmers RJ, van der Maarel SM, Czabotar PE, Dobson RC, Ritchie ME, Kay GF, Murphy JM, Blewitt ME. Genome-wide binding and mechanistic analyses of Smchd1-mediated epigenetic regulation. Proc Natl Acad Sci U S A. 2015 Jul 7;112(27):E3535-44. doi:, 10.1073/pnas.1504232112. Epub 2015 Jun 19. PMID:26091879 doi:http://dx.doi.org/10.1073/pnas.1504232112
- ↑ Brideau NJ, Coker H, Gendrel AV, Siebert CA, Bezstarosti K, Demmers J, Poot RA, Nesterova TB, Brockdorff N. Independent Mechanisms Target SMCHD1 to Trimethylated Histone H3 Lysine 9-Modified Chromatin and the Inactive X Chromosome. Mol Cell Biol. 2015 Dec;35(23):4053-68. doi: 10.1128/MCB.00432-15. Epub 2015 Sep , 21. PMID:26391951 doi:http://dx.doi.org/10.1128/MCB.00432-15
- ↑ Chen K, Dobson RC, Lucet IS, Young SN, Pearce FG, Blewitt ME, Murphy JM. The epigenetic regulator Smchd1 contains a functional GHKL-type ATPase domain. Biochem J. 2016 Jun 15;473(12):1733-44. doi: 10.1042/BCJ20160189. Epub 2016 Apr, 8. PMID:27059856 doi:http://dx.doi.org/10.1042/BCJ20160189
- ↑ Mason AG, Slieker RC, Balog J, Lemmers RJLF, Wong CJ, Yao Z, Lim JW, Filippova GN, Ne E, Tawil R, Heijmans BT, Tapscott SJ, van der Maarel SM. SMCHD1 regulates a limited set of gene clusters on autosomal chromosomes. Skelet Muscle. 2017 Jun 6;7(1):12. doi: 10.1186/s13395-017-0129-7. PMID:28587678 doi:http://dx.doi.org/10.1186/s13395-017-0129-7
- ↑ Wang CY, Jegu T, Chu HP, Oh HJ, Lee JT. SMCHD1 Merges Chromosome Compartments and Assists Formation of Super-Structures on the Inactive X. Cell. 2018 Jul 12;174(2):406-421.e25. doi: 10.1016/j.cell.2018.05.007. Epub 2018 , Jun 7. PMID:29887375 doi:http://dx.doi.org/10.1016/j.cell.2018.05.007
- ↑ Midic U, Vincent KA, Wang K, Lokken A, Severance AL, Ralston A, Knott JG, Latham KE. Novel key roles for structural maintenance of chromosome flexible domain containing 1 (Smchd1) during preimplantation mouse development. Mol Reprod Dev. 2018 Jul;85(7):635-648. doi: 10.1002/mrd.23001. PMID:29900695 doi:http://dx.doi.org/10.1002/mrd.23001
- ↑ Chen K, Birkinshaw RW, Gurzau AD, Wanigasuriya I, Wang R, Iminitoff M, Sandow JJ, Young SN, Hennessy PJ, Willson TA, Heckmann DA, Webb AI, Blewitt ME, Czabotar PE, Murphy JM. Crystal structure of the hinge domain of Smchd1 reveals its dimerization mode and nucleic acid-binding residues. Sci Signal. 2020 Jun 16;13(636). pii: 13/636/eaaz5599. doi:, 10.1126/scisignal.aaz5599. PMID:32546545 doi:http://dx.doi.org/10.1126/scisignal.aaz5599
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