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Polymerization of the SAM domain of TEL in leukemogenesis and transcriptional repression.

ABSTRACT: TEL is a transcriptional repressor that is a frequent target of chromosomal translocations in a large number of hematalogical malignancies. These rearrangements fuse a potent oligomerization module, the SAM domain of TEL, to a variety of tyrosine kinases or transcriptional regulatory proteins. The self-associating property of TEL-SAM is essential for cell transformation in many, if not all of these diseases. Here we show that the TEL-SAM domain forms a helical, head-to-tail polymeric structure held together by strong intermolecular contacts, providing the first clear demonstration that SAM domains can polymerize. Our results also suggest a mechanism by which SAM domains could mediate the spreading of transcriptional repression complexes along the chromosome.

SUBMITTER: Kim CA

PROVIDER: S-EPMC149168 | biostudies-literature | 2001 Aug

REPOSITORIES: biostudies-literature

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Polymerization of the SAM domain of TEL in leukemogenesis and transcriptional repression.

Kim C A CA Phillips M L ML Kim W W Gingery M M Tran H H HH Robinson M A MA Faham S S Bowie J U JU

The EMBO journal 20010801 15

TEL is a transcriptional repressor that is a frequent target of chromosomal translocations in a large number of hematalogical malignancies. These rearrangements fuse a potent oligomerization module, the SAM domain of TEL, to a variety of tyrosine kinases or transcriptional regulatory proteins. The self-associating property of TEL-SAM is essential for cell transformation in many, if not all of these diseases. Here we show that the TEL-SAM domain forms a helical, head-to-tail polymeric structure h ...[more]

PMID: 11483520

Similar Datasets

Native interface of the SAM domain polymer of TEL.

Project description:BackgroundTEL is a transcriptional repressor containing a SAM domain that forms a helical polymer. In a number of hematologic malignancies, chromosomal translocations lead to aberrant fusions of TEL-SAM to a variety of other proteins, including many tyrosine kinases. TEL-SAM polymerization results in constitutive activation of the tyrosine kinase domains to which it becomes fused, leading to cell transformation. Thus, inhibitors of TEL-SAM self-association could abrogate transformation in these cells. In previous work, we determined the structure of a mutant TEL-SAM polymer bearing a Val to Glu substitution in center of the subunit interface. It remained unclear how much the mutation affected the architecture of the polymer, however.ResultsHere we determine the structure of the native polymer interface. To accomplish this goal, we introduced mutations that block polymer extension, producing a heterodimer with a wild-type interface. We find that the structure of the wild-type polymer interface is quite similar to the mutant structure determined previously. With the structure of the native interface, it is possible to evaluate the potential for developing therapeutic inhibitors of the interaction. We find that the interacting surfaces of the protein are relatively flat, containing no obvious pockets for the design of small molecule inhibitors.ConclusionOur results confirm the architecture of the TEL-SAM polymer proposed previously based on a mutant structure. The fact that the interface contains no obvious potential binding pockets suggests that it may be difficult to find small molecule inhibitors to treat malignancies in this way.

| S-EPMC126206 | biostudies-literature

SAM domain polymerization links subnuclear clustering of PRC1 to silencing

2013-06-01 | E-GEOD-37530 | biostudies-arrayexpress

SAM domain polymerization links subnuclear clustering of PRC1 to silencing

2013-06-01 | GSE37530 | GEO

SAM domain polymerization links subnuclear clustering of PRC1 to silencing (Affymetrix)

Project description:Polycomb group (PcG) proteins mediate heritable but reversible silencing of developmental regulator genes by modifying their chromatin configuration. Accumulating evidence documents a role for PcG proteins in regulating higher order chromatin structures likely by their clustering, however, underlying mechanisms and its impact on transcriptional regulation remain obscure. In this study, we found that subnuclear clustering of PRC1 at canonical PcG target genes depended on head-to-tail polymerization property of SAM domain of Phc2 and likely Phc1. We show that Phc2-SAM polymerization limits the dynamic nature of PRC1, thereby promotes stable association of PRC1 with PcG target genes and contributes to their robust silencing. Our findings suggest a novel model by which SAM polymerization of Phc2 modulates the structural organization of PcG complexes to enable robust yet reversible PcG-mediated repression during development. Wild type and Phc2L307R/L307R MEFs were used for RNA extraction and hybridization on Affymetrix microarrays.

2013-06-01 | E-GEOD-37346 | biostudies-arrayexpress

SAM domain polymerization links subnuclear clustering of PRC1 to silencing (Affymetrix)

2013-06-01 | GSE37346 | GEO

SAM domain polymerization links subnuclear clustering of PRC1 to silencing (ChIP-chip)

Project description:Polycomb group (PcG) proteins mediate heritable but reversible silencing of developmental regulator genes by modifying their chromatin configuration. Accumulating evidence documents a role for PcG proteins in regulating higher order chromatin structures likely by their clustering, however, underlying mechanisms and its impact on transcriptional regulation remain obscure. In this study, we found that subnuclear clustering of PRC1 at canonical PcG target genes depended on head-to-tail polymerization property of SAM domain of Phc2 and likely Phc1. We show that Phc2-SAM polymerization limits the dynamic nature of PRC1, thereby promotes stable association of PRC1 with PcG target genes and contributes to their robust silencing. Our findings suggest a novel model by which SAM polymerization of Phc2 modulates the structural organization of PcG complexes to enable robust yet reversible PcG-mediated repression during development. ChIP on chip analysis was carried out using the Mouse Promoter ChIP-on-chip Microarray Set (G4490A, Agilent, Palo Alto, Calif., USA). MEFs were subjected to ChIP assay using a Ring1B antibody. Purified immunoprecipitated and input DNA was subjected to T7 RNA polymerase-based amplification. Labeling, hybridization and washing were carried out according to the Agilent mammalian ChIP-on-chip protocol (ver.9.0). Scanned images were quantified with Agilent Feature Extraction software under standard conditions.

2013-06-01 | E-GEOD-37526 | biostudies-arrayexpress

SAM domain polymerization links subnuclear clustering of PRC1 to silencing (ChIP-chip)

2013-06-01 | GSE37526 | GEO

SAM domain polymerization links subnuclear clustering of PRC1 to silencing (Ring1B ChIP-Seq)

2013-08-07 | E-GEOD-42801 | biostudies-arrayexpress

SAM domain polymerization links subnuclear clustering of PRC1 to silencing (Ring1B ChIP-Seq)

2013-08-07 | GSE42801 | GEO

Tankyrase Requires SAM Domain-Dependent Polymerization to Support Wnt-β-Catenin Signaling.

Project description:The poly(ADP-ribose) polymerase (PARP) Tankyrase (TNKS and TNKS2) is paramount to Wnt-β-catenin signaling and a promising therapeutic target in Wnt-dependent cancers. The pool of active β-catenin is normally limited by destruction complexes, whose assembly depends on the polymeric master scaffolding protein AXIN. Tankyrase, which poly(ADP-ribosyl)ates and thereby destabilizes AXIN, also can polymerize, but the relevance of these polymers has remained unclear. We report crystal structures of the polymerizing TNKS and TNKS2 sterile alpha motif (SAM) domains, revealing versatile head-to-tail interactions. Biochemical studies informed by these structures demonstrate that polymerization is required for Tankyrase to drive β-catenin-dependent transcription. We show that the polymeric state supports PARP activity and allows Tankyrase to effectively access destruction complexes through enabling avidity-dependent AXIN binding. This study provides an example for regulated signal transduction in non-membrane-enclosed compartments (signalosomes), and it points to novel potential strategies to inhibit Tankyrase function in oncogenic Wnt signaling.

| S-EPMC4980433 | biostudies-literature

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