| Structural highlights
Disease
[GRHL2_HUMAN] Autosomal dominant non-syndromic sensorineural deafness type DFNA. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.
Function
[GRHL2_HUMAN] Transcription factor playing an important role in primary neurulation and in epithelial development (PubMed:25152456). Binds directly to the consensus DNA sequence 5'-AACCGGTT-3' acting as an activator and repressor on distinct target genes (By similarity). During embryogenesis, plays unique and cooperative roles with GRHL3 in establishing distinct zones of primary neurulation. Essential for closure 3 (rostral end of the forebrain), functions cooperatively with GRHL3 in closure 2 (forebrain/midbrain boundary) and posterior neuropore closure (By similarity). Regulates epithelial morphogenesis acting as a target gene-associated transcriptional activator of apical junctional complex components. Up-regulates of CLDN3 and CLDN4, as well as of RAB25, which increases the CLDN4 protein and its localization at tight junctions (By similarity). Comprises an essential component of the transcriptional machinery that establishes appropriate expression levels of CLDN4 and CDH1 in different types of epithelia. Exhibits functional redundancy with GRHL3 in epidermal morphogenetic events and epidermal wound repair (By similarity). In lung, forms a regulatory loop with NKX2-1 that coordinates lung epithelial cell morphogenesis and differentiation (By similarity). In keratinocytes, plays a role in telomerase activation during cellular proliferation, regulates TERT expression by binding to TERT promoter region and inhibiting DNA methylation at the 5'-CpG island, possibly by interfering with DNMT1 enzyme activity (PubMed:19015635, PubMed:20938050). In addition, impairs keratinocyte differentiation and epidermal function by inhibiting the expression of genes clustered at the epidermal differentiation complex (EDC) as well as GRHL1 and GRHL3 through epigenetic mechanisms (PubMed:23254293).[UniProtKB:Q8K5C0][1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
Grainyhead (Grh)/CP2 transcription factors are highly conserved in multicellular organisms as key regulators of epithelial differentiation, organ development and skin barrier formation. In addition, they have been implicated as being tumor suppressors in a variety of human cancers. Despite their physiological importance, little is known about their structure and DNA binding mode. Here, we report the first structural study of mammalian Grh/CP2 factors. Crystal structures of the DNA-binding domains of grainyhead-like (Grhl) 1 and Grhl2 reveal a closely similar conformation with immunoglobulin-like core. Both share a common fold with the tumor suppressor p53, but differ in important structural features. The Grhl1 DNA-binding domain binds duplex DNA containing the consensus recognition element in a dimeric arrangement, supporting parsimonious target-sequence selection through two conserved arginine residues. We elucidate the molecular basis of a cancer-related mutation in Grhl1 involving one of these arginines, which completely abrogates DNA binding in biochemical assays and transcriptional activation of a reporter gene in a human cell line. Thus, our studies establish the structural basis of DNA target-site recognition by Grh transcription factors and reveal how tumor-associated mutations inactivate Grhl proteins. They may serve as points of departure for the structure-based development of Grh/CP2 inhibitors for therapeutic applications.
Structural basis of gene regulation by the Grainyhead/CP2 transcription factor family.,Ming Q, Roske Y, Schuetz A, Walentin K, Ibraimi I, Schmidt-Ott KM, Heinemann U Nucleic Acids Res. 2018 Jan 4. pii: 4788346. doi: 10.1093/nar/gkx1299. PMID:29309642[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Kang X, Chen W, Kim RH, Kang MK, Park NH. Regulation of the hTERT promoter activity by MSH2, the hnRNPs K and D, and GRHL2 in human oral squamous cell carcinoma cells. Oncogene. 2009 Jan 29;28(4):565-74. doi: 10.1038/onc.2008.404. Epub 2008 Nov 17. PMID:19015635 doi:http://dx.doi.org/10.1038/onc.2008.404
- ↑ Chen W, Dong Q, Shin KH, Kim RH, Oh JE, Park NH, Kang MK. Grainyhead-like 2 enhances the human telomerase reverse transcriptase gene expression by inhibiting DNA methylation at the 5'-CpG island in normal human keratinocytes. J Biol Chem. 2010 Dec 24;285(52):40852-63. doi: 10.1074/jbc.M110.103812. Epub, 2010 Oct 11. PMID:20938050 doi:http://dx.doi.org/10.1074/jbc.M110.103812
- ↑ Werth M, Walentin K, Aue A, Schonheit J, Wuebken A, Pode-Shakked N, Vilianovitch L, Erdmann B, Dekel B, Bader M, Barasch J, Rosenbauer F, Luft FC, Schmidt-Ott KM. The transcription factor grainyhead-like 2 regulates the molecular composition of the epithelial apical junctional complex. Development. 2010 Nov;137(22):3835-45. doi: 10.1242/dev.055483. PMID:20978075 doi:http://dx.doi.org/10.1242/dev.055483
- ↑ Chen W, Xiao Liu Z, Oh JE, Shin KH, Kim RH, Jiang M, Park NH, Kang MK. Grainyhead-like 2 (GRHL2) inhibits keratinocyte differentiation through epigenetic mechanism. Cell Death Dis. 2012 Dec 20;3:e450. doi: 10.1038/cddis.2012.190. PMID:23254293 doi:http://dx.doi.org/10.1038/cddis.2012.190
- ↑ Petrof G, Nanda A, Howden J, Takeichi T, McMillan JR, Aristodemou S, Ozoemena L, Liu L, South AP, Pourreyron C, Dafou D, Proudfoot LE, Al-Ajmi H, Akiyama M, McLean WH, Simpson MA, Parsons M, McGrath JA. Mutations in GRHL2 result in an autosomal-recessive ectodermal Dysplasia syndrome. Am J Hum Genet. 2014 Sep 4;95(3):308-14. doi: 10.1016/j.ajhg.2014.08.001. Epub, 2014 Aug 21. PMID:25152456 doi:http://dx.doi.org/10.1016/j.ajhg.2014.08.001
- ↑ Wilanowski T, Tuckfield A, Cerruti L, O'Connell S, Saint R, Parekh V, Tao J, Cunningham JM, Jane SM. A highly conserved novel family of mammalian developmental transcription factors related to Drosophila grainyhead. Mech Dev. 2002 Jun;114(1-2):37-50. PMID:12175488
- ↑ Ming Q, Roske Y, Schuetz A, Walentin K, Ibraimi I, Schmidt-Ott KM, Heinemann U. Structural basis of gene regulation by the Grainyhead/CP2 transcription factor family. Nucleic Acids Res. 2018 Jan 4. pii: 4788346. doi: 10.1093/nar/gkx1299. PMID:29309642 doi:http://dx.doi.org/10.1093/nar/gkx1299
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