SALL1, the gene mutated in Townes-Brocks syndrome, encodes a transcriptional repressor which interacts with TRF1/PIN2 and localizes to pericentromeric heterochromatin

Institute of Human Genetics, University of Göttingen, Heinrich-Düker-Weg 12, 37073 Göttingen, Germany.
Human Molecular Genetics (Impact Factor: 6.39). 01/2002; 10(26):3017-24.
Source: PubMed


The Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited malformation syndrome presenting as an association of imperforate anus, triphalangeal and supernumerary thumbs, malformed ears and sensorineural hearing loss. Mutations in SALL1, a gene mapping to 16q12.1, were identified as a cause for TBS. To elucidate how SALL1 mutations lead to TBS, we have performed a series of functional studies with the SALL1 protein. Using epifluorescence and confocal microscopy it could be shown that a GFP-SALL1 fusion protein localizes to chromocenters and smaller heterochromatin foci in transiently transfected NIH-3T3 cells. Chromocenters consist of clustered pericentromeric heterochromatin and contain telomere sequences. Indirect immunofluorescence revealed a partial colocalization of GFP-SALL1 with M31, the mouse homolog of the Drosophila heterochromatic protein HP1. It was further demonstrated that SALL1 acts as a strong transcriptional repressor in mammalian cells. Transcriptional repression could not be relieved by the addition of the histone deacetylase inhibitor Trichostatin-A. In a yeast two-hybrid screen we identified PIN2, an isoform of telomere-repeat-binding factor 1 (TRF1), as an interaction partner of SALL1, and showed that the N-terminus of SALL1 is not necessary for the interaction with PIN2/TRF1. The interaction was confirmed in vitro in a GST-pulldown assay. The association of the developmental regulator SALL1 with heterochromatin is striking and unexpected. Our results propose an involvement of SALL1 in the regulation of higher order chromatin structures and indicate that the protein might be a component of a distinct heterochromatin-dependent silencing process. We have also provided new evidence that there is a close functional link between the centromeric and telomeric heterochromatin domains not only in Drosophila and yeast, but also in mammalian cells.

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Available from: Juergen Kohlhase, Mar 27, 2015
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    • "– Specific binding to telomeric ds DNA through a Myb/SANT/Telobox domain (NMR: pdb 1IV6; X-ray: pdb 1WOT) – Homodimerization TRFH domain (pdb 1H6O) – Binds telomeric dsDNA as a dimer [136] [157] – Bends DNA [136] [157] – Creates DNA synapsis [156] – Facilitates ssDNA invasion into duplex DNA [80] – Regulates Werner activity in vitro [192] NM23-H2 [193], SALL1 [194], TIN2, PINX1, ATM, EB1, MMS21, NS, FBX4, Tankyrase1 and 2 [195], BLM [196], PML3 [197]; SA1 [198] – Telomere length regulation [77] [199] – Telomere replication [32] [200] – End protection [199] [200] – Mitosis[199] [200] [201] [202] "
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    • "The data presented here showing that HP1 proteins are also required for APB formation raise the question of what role they play in this process, and whether shelterin and MRN proteins may interact with HP1 proteins at telomeres . HP1 proteins are usually recruited to chromatin through their affinity for trimethylated H3K9 residues (Lachner et al., 2001; Garcia-Cao et al., 2004), but it is also possible that this occurs through the interactions between TRF1 and the HP1-interacting developmental regulator SALL1 (Netzer et al., 2001) or between TIN2 and HP1 (Kaminker et al., 2005). Another interesting Figure 7. HP1 localization in APBs and effects on APB formation of HP1 depletion. "
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    • "Over-expressed Sall1 protein has been reported to localize to pericentric heterochromatin in cultured cell lines (Netzer et al. 2001; Kiefer et al. 2002; Sato et al. 2004). However, the localization of endogenous Sall1 remains unclear. "
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    ABSTRACT: The Spalt (sal) gene family is conserved from Drosophila to humans. Mutations of human SALL1 cause Townes-Brocks syndrome, with features of ear, limb, anal, renal and heart anomalies. Sall1, a murine homolog of SALL1, is essential for kidney formation, and both Sall1 and SALL1 localize to heterochromatin in the nucleus. Here, we present a molecular mechanism for the heterochromatin localization of Sall1. Mutation analyses revealed that the 7th-10th C-terminal double zinc finger motifs were required for the localization. A recombinant protein of the most C-terminal double zinc finger (9th-10th) bound to specific A/T-rich sequences. Furthermore, Sall1 associated with A/T-rich sequences of the major satellite DNA in heterochromatin. Thus Sall1 may bind to A/T-rich sequences of the major satellite DNA via its C-terminal double zinc fingers, thereby mediating its localization to heterochromatin.
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