Alternative titles; symbols
HGNC Approved Gene Symbol: HLTF
Cytogenetic location: 3q24 Genomic coordinates (GRCh38) : 3:149,030,063-149,086,533 (from NCBI)
The S. cerevisiae SNF2/SWI2 protein and its homologs are required for optimal regulated transcription by many gene-specific activators. SNF2/SWI2 is thought to actively dissociate nucleosomes to facilitate binding of regulatory proteins to their control regions on the DNA. See 603111. By screening a HeLa cell expression library with sequences from the initiator region of the HIV-1 promoter, Sheridan et al. (1995) isolated cDNAs encoding SMARCA3, which they called HIP116. The predicted 1,009-amino acid protein had homology to members of the SNF2/SWI2-related protein family. The primary regions of homology include 7 consecutive motifs characteristic of ATPases and DNA helicases. In addition, SMARCA3 contains a RING finger motif and a putative nuclear localization signal. The N-terminal region of SMARCA3 houses a DNA binding domain that does not include the RING finger. SMARCA3 bound the HIV-1 promoter and SV40 enhancer in vitro and displayed DNA-dependent ATPase activity that was strongly stimulated by SV40 enhancer. Sheridan et al. (1995) suggested that SMARCA3 affects transcription by acting as a DNA binding site-specific ATPase.
The proximal promoter of the PAI1 (173360) gene contains 2 regulatory sequences, Box A and Box B, that mediate the response to phorbol esters. Ding et al. (1996) identified SMARCA3 as a 114-kD protein (helicase-like transcription factor or HLTF) that selectively interacts with Box B. Antibodies against SMARCA3 recognized 114- and 120-kD proteins in HeLa cell nuclear extracts. Only the 114-kD protein was active in mediating the basal activity of the PAI1 promoter in transient expression assays. The authors demonstrated that this shorter variant arose from use of an alternative translation initiation site. Using immunofluorescence, Ding et al. (1996) found that SMARCA3 is a nuclear protein homogeneously distributed throughout the nucleoplasm. Northern blot analysis revealed that SMARCA3 is expressed as 4.5- and 5.5-kb mRNAs in various human tissues.
Chromatin remodeling enzymes are implicated in a variety of important cellular functions. Various components of chromatin remodeling complexes, including several members of the SWI/SNF family, are disrupted in cancer. Moinova et al. (2002) identified the HLTF gene (SMARCA3) as a target for gene inactivation in colon cancer. Loss of HLTF expression accompanied by HLTF promoter methylation was noted in 9 of 34 colon cancer cell lines. In these cell lines, HLTF expression was restored by treatment with the demethylating agent 5-azacytidine. In further studies of primary colon cancer tissues, HLTF methylation was detected in 27 of 63 cases (43%). No methylation of HLTF was detected in breast or lung cancers, suggesting selection for HLTF methylation in colonic malignancies. Transfection of HLTF suppressed 75% of colon growth in each of 3 different HLTF-deficient cell lines, but showed no suppressive effect in any of 3 HLTF-proficient cell lines. These findings showed that HLTF is a common target for methylation and epigenetic gene silencing in colon cancer and suggested HLTF as a candidate colon cancer suppressor gene.
Using mice and mouse cells and constructs, Oh et al. (2013) found that p11 (S100A10; 114085) and its binding partner, annexin A2 (ANXA2; 151740), stabilized each other and engaged in a ternary complex with Smarca3. Determination of crystal structure revealed that Anxa2 and p11 formed symmetrical dimers that bound 2 Smarca3 peptides aligned in a head-to-head arrangement. Smarca3 interacted with elements of both Anxa2 and p11. Inclusion of Smarca3 in the complex induced a conformational change in Anxa2-p11 that followed an induced-fit model. Smarca3 bound a B-box element in DNA, and inclusion of Anxa2-p11 increased binding of Smarca3 to an immobilized B-box element. Reporter gene assays in mouse N2A neuroblastoma cells revealed that Anxa2-p11 potentiated transcriptional activation by Smarca3. In cells, interaction of Smarca3 with Anxa2-p11 anchored Smarca3 to the nuclear matrix. Using knockout mice, Oh et al. (2013) showed that hippocampal p11 and Smarca3 were required for behavioral responses to selective serotonin reuptake inhibitors used as antidepressants.
By analysis of somatic cell hybrids and by FISH, Lin et al. (1995) mapped the SMARCA3 gene to 3q25.1-q26.1.
Ding, H., Descheemaeker, K., Marynen, P., Nelles, L., Carvalho, T., Carmo-Fonseca, M., Collen, D., Belayew, A. Characterization of a helicase-like transcription factor involved in the expression of the human plasminogen activator inhibitor-1 gene. DNA Cell Biol. 15: 429-442, 1996. [PubMed: 8672239] [Full Text: https://doi.org/10.1089/dna.1996.15.429]
Lin, Y., Sheridan, P. L., Jones, K. A., Evans, G. A. The HIP116 SNF2/SWI2-related transcription factor gene (SNF2L3) is located on human chromosome 3q25.1-q26.1 Genomics 27: 381-382, 1995. [PubMed: 7558014] [Full Text: https://doi.org/10.1006/geno.1995.1064]
Moinova, H. R., Chen, W.-D., Shen, L., Smiraglia, D., Olechnowicz, J., Ravi, L., Kasturi, L., Myeroff, L., Plass, C., Parsons, R., Minna, J., Willson, J. K. V., Green, S. B., Issa, J.-P., Markowitz, S. D. HLTF gene silencing in human colon cancer. Proc. Nat. Acad. Sci. 99: 4562-4567, 2002. Note: Erratum: Proc. Nat. Acad. Sci. 99: 9081 only, 2002. [PubMed: 11904375] [Full Text: https://doi.org/10.1073/pnas.062459899]
Oh, Y.-S., Gao, P., Lee, K.-W., Ceglia, I., Seo, J.-S., Zhang, X., Ahn, J.-H., Chait, B. T., Patel, D. J., Kim, Y., Greengard, P. SMARCA3, a chromatin-remodeling factor, is required for p11-dependent antidepressant action. Cell 152: 831-843, 2013. [PubMed: 23415230] [Full Text: https://doi.org/10.1016/j.cell.2013.01.014]
Sheridan, P. L., Schorpp, M., Voz, M. L., Jones, K. A. Cloning of an SNF2/SWI2-related protein that binds specifically to the SPH motifs of the SV40 enhancer and to the HIV-1 promoter. J. Biol. Chem. 270: 4575-4587, 1995. [PubMed: 7876228] [Full Text: https://doi.org/10.1074/jbc.270.9.4575]