9t2g

Structural highlights

Disease

ZMYD8_HUMAN Mutations in ZMYND8 may be the cause of syndromic intellectual disability with variable cardiovascular, ophthalmologic and minor skeletal anomalies.^[1]

Function

ZMYD8_HUMAN Chromatin reader that recognizes dual histone modifications such as histone H3.1 dimethylated at 'Lys-36' and histone H4 acetylated at 'Lys-16' (H3.1K36me2-H4K16ac) and histone H3 methylated at 'Lys-4' and histone H4 acetylated at 'Lys-14' (H3K4me1-H3K14ac) (PubMed:26655721, PubMed:27477906, PubMed:31965980, PubMed:36064715). May act as a transcriptional corepressor for KDM5D by recognizing the dual histone signature H3K4me1-H3K14ac (PubMed:27477906). May also act as a transcriptional corepressor for KDM5C and EZH2 (PubMed:33323928). Recognizes acetylated histone H4 and recruits the NuRD chromatin remodeling complex to damaged chromatin for transcriptional repression and double-strand break repair by homologous recombination (PubMed:25593309, PubMed:27732854, PubMed:30134174). Also activates transcription elongation by RNA polymerase II through recruiting the P-TEFb complex to target promoters (PubMed:26655721, PubMed:30134174). Localizes to H3.1K36me2-H4K16ac marks at all-trans-retinoic acid (ATRA)-responsive genes and positively regulates their expression (PubMed:26655721). Promotes neuronal differentiation by associating with regulatory regions within the MAPT gene, to enhance transcription of a protein-coding MAPT isoform and suppress the non-coding MAPT213 isoform (PubMed:30134174, PubMed:35916866, PubMed:36064715). Suppresses breast cancer, and prostate cancer cell invasion and metastasis (PubMed:27477906, PubMed:31965980, PubMed:33323928).^{[2] [3] [4] [5] [6] [7] [8] [9] [10]}

References

1. ↑ Dias KR, Carlston CM, Blok LER, De Hayr L, Nawaz U, Evans CA, Bayrak-Toydemir P, Htun S, Zhu Y, Ma A, Lynch SA, Moorwood C, Stals K, Ellard S, Bainbridge MN, Friedman J, Pappas JG, Rabin R, Nowak CB, Douglas J, Wilson TE, Guillen Sacoto MJ, Mullegama SV, Palculict TB, Kirk EP, Pinner JR, Edwards M, Montanari F, Graziano C, Pippucci T, Dingmann B, Glass I, Mefford HC, Shimoji T, Suzuki T, Yamakawa K, Streff H, Schaaf CP, Slavotinek AM, Voineagu I, Carey JC, Buckley MF, Schenck A, Harvey RJ, Roscioli T. De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations. Genet Med. 2022 Sep;24(9):1952-1966. PMID:35916866 doi:10.1016/j.gim.2022.06.001
2. ↑ Gong F, Chiu LY, Cox B, Aymard F, Clouaire T, Leung JW, Cammarata M, Perez M, Agarwal P, Brodbelt JS, Legube G, Miller KM. Screen identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination. Genes Dev. 2015 Jan 15;29(2):197-211. PMID:25593309 doi:10.1101/gad.252189.114
3. ↑ Adhikary S, Sanyal S, Basu M, Sengupta I, Sen S, Srivastava DK, Roy S, Das C. Selective Recognition of H3.1K36 Dimethylation/H4K16 Acetylation Facilitates the Regulation of All-trans-retinoic Acid (ATRA)-responsive Genes by Putative Chromatin Reader ZMYND8. J Biol Chem. 2016 Feb 5;291(6):2664-81. PMID:26655721 doi:10.1074/jbc.M115.679985
4. ↑ Li N, Li Y, Lv J, Zheng X, Wen H, Shen H, Zhu G, Chen TY, Dhar SS, Kan PY, Wang Z, Shiekhattar R, Shi X, Lan F, Chen K, Li W, Li H, Lee MG. ZMYND8 Reads the Dual Histone Mark H3K4me1-H3K14ac to Antagonize the Expression of Metastasis-Linked Genes. Mol Cell. 2016 Aug 4;63(3):470-84. doi: 10.1016/j.molcel.2016.06.035. Epub 2016, Jul 28. PMID:27477906 doi:http://dx.doi.org/10.1016/j.molcel.2016.06.035
5. ↑ Spruijt CG, Luijsterburg MS, Menafra R, Lindeboom RG, Jansen PW, Edupuganti RR, Baltissen MP, Wiegant WW, Voelker-Albert MC, Matarese F, Mensinga A, Poser I, Vos HR, Stunnenberg HG, van Attikum H, Vermeulen M. ZMYND8 Co-localizes with NuRD on Target Genes and Regulates Poly(ADP-Ribose)-Dependent Recruitment of GATAD2A/NuRD to Sites of DNA Damage. Cell Rep. 2016 Oct 11;17(3):783-798. PMID:27732854 doi:10.1016/j.celrep.2016.09.037
6. ↑ Ghosh K, Tang M, Kumari N, Nandy A, Basu S, Mall DP, Rai K, Biswas D. Positive Regulation of Transcription by Human ZMYND8 through Its Association with P-TEFb Complex. Cell Rep. 2018 Aug 21;24(8):2141-2154.e6. PMID:30134174 doi:10.1016/j.celrep.2018.07.064
7. ↑ Mukherjee S, Sen S, Adhikary S, Sengupta A, Mandal P, Dasgupta D, Chakrabarti P, Roy S, DAS C. A novel role of tumor suppressor ZMYND8 in inducing differentiation of breast cancer cells through its dual-histone binding function. J Biosci. 2020;45:2 PMID:31965980
8. ↑ Mukherjee S, Adhikary S, Gadad SS, Mondal P, Sen S, Choudhari R, Singh V, Adhikari S, Mandal P, Chaudhuri S, Sengupta A, Lakshmanaswamy R, Chakrabarti P, Roy S, Das C. Suppression of poised oncogenes by ZMYND8 promotes chemo-sensitization. Cell Death Dis. 2020 Dec 15;11(12):1073. PMID:33323928 doi:10.1038/s41419-020-03129-x
9. ↑ Dias KR, Carlston CM, Blok LER, De Hayr L, Nawaz U, Evans CA, Bayrak-Toydemir P, Htun S, Zhu Y, Ma A, Lynch SA, Moorwood C, Stals K, Ellard S, Bainbridge MN, Friedman J, Pappas JG, Rabin R, Nowak CB, Douglas J, Wilson TE, Guillen Sacoto MJ, Mullegama SV, Palculict TB, Kirk EP, Pinner JR, Edwards M, Montanari F, Graziano C, Pippucci T, Dingmann B, Glass I, Mefford HC, Shimoji T, Suzuki T, Yamakawa K, Streff H, Schaaf CP, Slavotinek AM, Voineagu I, Carey JC, Buckley MF, Schenck A, Harvey RJ, Roscioli T. De Novo ZMYND8 variants result in an autosomal dominant neurodevelopmental disorder with cardiac malformations. Genet Med. 2022 Sep;24(9):1952-1966. PMID:35916866 doi:10.1016/j.gim.2022.06.001
10. ↑ Adhikary S, Singh V, Choudhari R, Yang B, Adhikari S, Ramos EI, Chaudhuri S, Roy S, Gadad SS, Das C. ZMYND8 suppresses MAPT213 LncRNA transcription to promote neuronal differentiation. Cell Death Dis. 2022 Sep 5;13(9):766. PMID:36064715 doi:10.1038/s41419-022-05212-x