| Structural highlights
Disease
DNM3B_HUMAN ICF syndrome. The disease is caused by mutations affecting the gene represented in this entry.[1] [2] [3] [4] [5]
Function
DNM3B_HUMAN Required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development. DNA methylation is coordinated with methylation of histones. May preferentially methylates nucleosomal DNA within the nucleosome core region. May function as transcriptional co-repressor by associating with CBX4 and independently of DNA methylation. Seems to be involved in gene silencing (By similarity). In association with DNMT1 and via the recruitment of CTCFL/BORIS, involved in activation of BAG1 gene expression by modulating dimethylation of promoter histone H3 at H3K4 and H3K9. Isoforms 4 and 5 are probably not functional due to the deletion of two conserved methyltransferase motifs. Function as transcriptional corepressor by associating with ZHX1.[6] [7] [8] [9]
Publication Abstract from PubMed
DNA methyltransferase DNMT3B plays an essential role in establishment of DNA methylation during embryogenesis. Mutations of DNMT3B are associated with human diseases, notably the immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome. How ICF mutations affect DNMT3B activity is not fully understood. Here we report the homo-oligomeric structure of DNMT3B methyltransferase domain, providing insight into DNMT3B-mediated DNA methylation in embryonic stem cells where the functional regulator DNMT3L is dispensable. The interplay between one of the oligomer interfaces (FF interface) and the catalytic loop renders DNMT3B homo-oligomer a conformation and activity distinct from the DNMT3B-DNMT3L heterotetramer, and a greater vulnerability to certain ICF mutations. Biochemical and cellular analyses further reveal that the ICF mutations of FF interface impair the DNA binding and heterochromatin targeting of DNMT3B, leading to reduced DNA methylation in cells. Together, this study provides a mechanistic understanding of DNMT3B-mediated DNA methylation and its dysregulation in disease.
Structure of DNMT3B homo-oligomer reveals vulnerability to impairment by ICF mutations.,Gao L, Guo Y, Biswal M, Lu J, Yin J, Fang J, Chen X, Shao Z, Huang M, Wang Y, Wang GG, Song J Nat Commun. 2022 Jul 22;13(1):4249. doi: 10.1038/s41467-022-31933-w. PMID:35869095[10]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Xu GL, Bestor TH, Bourc'his D, Hsieh CL, Tommerup N, Bugge M, Hulten M, Qu X, Russo JJ, Viegas-Pequignot E. Chromosome instability and immunodeficiency syndrome caused by mutations in a DNA methyltransferase gene. Nature. 1999 Nov 11;402(6758):187-91. PMID:10647011 doi:https://dx.doi.org/10.1038/46052
- ↑ Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999 Oct 29;99(3):247-57. PMID:10555141
- ↑ Hansen RS, Wijmenga C, Luo P, Stanek AM, Canfield TK, Weemaes CM, Gartler SM. The DNMT3B DNA methyltransferase gene is mutated in the ICF immunodeficiency syndrome. Proc Natl Acad Sci U S A. 1999 Dec 7;96(25):14412-7. PMID:10588719
- ↑ Wijmenga C, Hansen RS, Gimelli G, Bjorck EJ, Davies EG, Valentine D, Belohradsky BH, van Dongen JJ, Smeets DF, van den Heuvel LP, Luyten JA, Strengman E, Weemaes C, Pearson PL. Genetic variation in ICF syndrome: evidence for genetic heterogeneity. Hum Mutat. 2000 Dec;16(6):509-17. PMID:11102980 doi:<509::AID-HUMU8>3.0.CO;2-V https://dx.doi.org/10.1002/1098-1004(200012)16:6<509::AID-HUMU8>3.0.CO;2-V
- ↑ Jiang YL, Rigolet M, Bourc'his D, Nigon F, Bokesoy I, Fryns JP, Hulten M, Jonveaux P, Maraschio P, Megarbane A, Moncla A, Viegas-Pequignot E. DNMT3B mutations and DNA methylation defect define two types of ICF syndrome. Hum Mutat. 2005 Jan;25(1):56-63. PMID:15580563 doi:https://dx.doi.org/10.1002/humu.20113
- ↑ Vire E, Brenner C, Deplus R, Blanchon L, Fraga M, Didelot C, Morey L, Van Eynde A, Bernard D, Vanderwinden JM, Bollen M, Esteller M, Di Croce L, de Launoit Y, Fuks F. The Polycomb group protein EZH2 directly controls DNA methylation. Nature. 2006 Feb 16;439(7078):871-4. Epub 2005 Dec 14. PMID:16357870 doi:10.1038/nature04431
- ↑ Kim SH, Park J, Choi MC, Kim HP, Park JH, Jung Y, Lee JH, Oh DY, Im SA, Bang YJ, Kim TY. Zinc-fingers and homeoboxes 1 (ZHX1) binds DNA methyltransferase (DNMT) 3B to enhance DNMT3B-mediated transcriptional repression. Biochem Biophys Res Commun. 2007 Apr 6;355(2):318-23. Epub 2007 Feb 8. PMID:17303076 doi:https://dx.doi.org/10.1016/j.bbrc.2007.01.187
- ↑ Sun L, Huang L, Nguyen P, Bisht KS, Bar-Sela G, Ho AS, Bradbury CM, Yu W, Cui H, Lee S, Trepel JB, Feinberg AP, Gius D. DNA methyltransferase 1 and 3B activate BAG-1 expression via recruitment of CTCFL/BORIS and modulation of promoter histone methylation. Cancer Res. 2008 Apr 15;68(8):2726-35. PMID:18413740 doi:68/8/2726
- ↑ Kim SH, Park J, Choi MC, Park JH, Kim HP, Lee JH, Oh DY, Im SA, Bang YJ, Kim TY. DNA methyltransferase 3B acts as a co-repressor of the human polycomb protein hPc2 to repress fibroblast growth factor receptor 3 transcription. Int J Biochem Cell Biol. 2008;40(11):2462-71. doi: 10.1016/j.biocel.2008.04.018. , Epub 2008 May 18. PMID:18567530 doi:https://dx.doi.org/10.1016/j.biocel.2008.04.018
- ↑ Gao L, Guo Y, Biswal M, Lu J, Yin J, Fang J, Chen X, Shao Z, Huang M, Wang Y, Wang GG, Song J. Structure of DNMT3B homo-oligomer reveals vulnerability to impairment by ICF mutations. Nat Commun. 2022 Jul 22;13(1):4249. doi: 10.1038/s41467-022-31933-w. PMID:35869095 doi:https://dx.doi.org/10.1038/s41467-022-31933-w
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