Alternative titles; symbols
HGNC Approved Gene Symbol: SAFB
Cytogenetic location: 19p13.3 Genomic coordinates (GRCh38) : 19:5,623,083-5,668,478 (from NCBI)
Eukaryotic chromatin is organized in a higher order structure consisting of thousands of discrete, topologically constrained loop domains. These loops are fixed at their bases to a network composed of proteins and RNA that is generally referred to as the nuclear matrix or scaffold. Evidence suggests that a tight binding of chromatin to the nuclear scaffold is not only important for the compaction of the chromatin fiber, but is also involved in many aspects of nucleic acid metabolism. Attachment of chromatin to the nuclear scaffold appears to occur via specialized DNA elements called scaffold attachment regions (SARs). Romig et al. (1992) identified 4 nuclear proteins, termed scaffold attachment factors (SAFs) A (602869), B, C, and D, that specifically interact with SAR DNA elements. Renz and Fackelmayer (1996) purified the SAFB protein from HeLa cell nuclear extracts. SAFB is a monomer with a molecular mass of 150 kD by SDS-PAGE. It is a DNA-binding protein that has a high specificity for SAR DNA elements. Biochemical fractionation studies demonstrated that SAFB is a component of chromatin but not of the nuclear matrix. By screening a human HeLa cell cDNA expression library with antibodies against purified SAFB, Renz and Fackelmayer (1996) isolated partial cDNAs encoding SAFB. Northern blot analysis detected a 3.4-kb SAFB transcript in all human tissues examined.
Heat-shock protein-27 (HSP27; 602195) is an estrogen-regulated protein that enhances the proliferation and drug resistance of breast cancer. Its promoter region contains an imperfect estrogen response element and a TATA box. Oesterreich et al. (1997) identified HET as an HSP27 promoter-binding protein in gel retardation assays. They cloned a partial HET cDNA by screening a human breast cancer cell (MCF-7) cDNA expression library with the promoter region of HSP27. Using this partial cDNA to screen a second MCF-7 cDNA library, the authors isolated a full-length HET cDNA. Oesterreich et al. (1997) noted that the HET gene is probably identical to the SAFB gene studied by Renz and Fackelmayer (1996). The predicted 915-amino acid HET protein (GenBank 2828537) is highly charged, with 221 negatively charged and 164 positively charged residues, and contains several potential phosphorylation, glycosylation, and myristylation sites. By SDS-PAGE and Southwestern blot analysis of MCF-7 extracts, HET had a molecular mass of 120 kD, which is higher than its calculated mass of 100 kD. Oesterreich et al. (1997) showed that the HET protein localizes to the nuclear matrix of various breast cancer cell lines, a result that disagrees with the localization studies of Renz and Fackelmayer (1996).
Oesterreich et al. (1997) found that overexpression of HET decreased the activity of the HSP27 promoter in various breast cancer cell lines.
Using chromatin immunoprecipitation (ChIP)-on-chip and gene expression array analyses of MCF7 human breast cancer cells, Hammerich-Hille et al. (2010) identified 541 SAFB1- and/or SAFB2 (608066)-binding sites in promoters of known genes. Enrichment of binding sites was observed in regions of chromosomes 1 and 6 containing histone gene clusters. Gene expression array analysis revealed upregulation of most target genes following knockdown of SAFB1 or SAFB2 via small interfering RNA. In general, SAFB2 regulated fewer genes than SAFB1, and there was relatively little overlap in the genes regulated by SAFB1 and SAFB2. Of all the genes regulated by SAFB1, 38% were involved in immune regulation, 28% were involved in cell signaling, and 11% were involved in apoptosis. SAFB1 knockdown resulted in about 11-fold increased expression of C8ORF4 (607702) and GABBR1 (603540).
Using a FLASH RNA-protein interaction screen in HEK293 cells, Ilik et al. (2024) demonstrated that SAFB1, SAFB2, and SAFB-like transcriptional modulator (SLTM; 620992) bound to L1 RNA. By binding to L1 RNA, the SAFB proteins retained L1 RNA in the nucleus, thereby preventing L1 retrotransposition into new genetic loci. SAFB proteins also maintained splicing integrity by preventing exonization of previously integrated transposable elements (TEs). SAFB proteins could play this unique dual role because they bound to the conserved adenosine-rich coding sequences of L1. The suppressive activity of SAFB extended to tissue-specific, giant protein-coding cassette exons, nested genes, and Tigger DNA transposons. Moreover, SAFB also suppressed LTR/ERV elements in species in which they were still active, such as mice and flies. A significant subset of splicing events suppressed by SAFB in somatic cells was activated in testis, coinciding with low SAFB expression in postmeiotic spermatids. The authors concluded that SAFB proteins form an RNA-based, pattern-guided, nonadaptive defense system against TEs in the soma, complementing the RNA-based, adaptive Piwi-interacting RNA pathway (see 605571) of the germline.
Using somatic cell hybrid analysis and fluorescence in situ hybridization, DuPont et al. (1997) mapped the SAFB gene to 19p13.3-p13.2.
DuPont, B. R., Garcia, D. K., Sullivan, T. M., Naylor, S. L., Oesterreich, S. Assignment of the SAFB encoding Hsp27 ERE-TATA binding protein (HET)/scaffold attachment factor B (SAF-B) to human chromosome 19 band p13. Cytogenet. Cell Genet. 79: 284-285, 1997. [PubMed: 9605873] [Full Text: https://doi.org/10.1159/000134744]
Hammerich-Hille, S., Kaipparettu, B. A., Tsimelzon, A., Creighton, C. J., Jiang, S., Polo, J. M., Melnick, A., Meyer, R., Oesterreich, S. SAFB1 mediates repression of immune regulators and apoptotic genes in breast cancer cells. J. Biol. Chem. 285: 3608-3616, 2010. [PubMed: 19901029] [Full Text: https://doi.org/10.1074/jbc.M109.066431]
Ilik, I. A., Glazar, P., Tse, K., Brandl, B., Meierhofer, D., Muller, F. J., Smith, Z. D., Aktas, T. Autonomous transposons tune their sequences to ensure somatic suppression. Nature 626: 1116-1124, 2024. [PubMed: 38355802] [Full Text: https://doi.org/10.1038/s41586-024-07081-0]
Oesterreich, S., Lee, A. V., Sullivan, T. M., Samuel, S. K., Davie, J. R., Fuqua, S. A. W. Novel nuclear matrix protein HET binds to and influences activity of the HSP27 promoter in human breast cancer cells. J. Cell. Biochem. 67: 275-286, 1997. [PubMed: 9328833]
Renz, A., Fackelmayer, F. O. Purification and molecular cloning of the scaffold attachment factor B (SAF-B), a novel human nuclear protein that specifically binds to S/MAR-DNA. Nucleic Acids Res. 24: 843-849, 1996. [PubMed: 8600450] [Full Text: https://doi.org/10.1093/nar/24.5.843]
Romig, H., Fackelmayer, F. O., Renz, A., Ramsperger, U., Richter, A. Characterization of SAF-A, a novel nuclear DNA binding protein from HeLa cells with high affinity for nuclear matrix/scaffold attachment DNA elements. EMBO J. 11: 3431-3440, 1992. [PubMed: 1324173] [Full Text: https://doi.org/10.1002/j.1460-2075.1992.tb05422.x]