HBP1 and Mad1 repressors bind the Sin3 corepressor PAH2 domain with opposite helical orientations

Swanson, Kurtis J.; Knoepfler, Paul S.; Huang, Kai; Kang, Richard S.; Cowley, Shaun M.; Laherty, Carol D.; Eisenman, Robert N.; Radhakrishnan, Ishwar

doi:10.1038/nsmb798

Cited by 67 publications

(97 citation statements)

References 49 publications

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“…As shown in Figure 3b, HBP1 is a member of the sequence-specific HMG box family of transcriptional factors with a central repression domain (amino acids 191-400) and a C-terminal HMG box DNA-bindingdomain (amino acids 431-509), as well as retinoblastoma and p38 MAPK-binding regulatory regions Swanson et al, 2004;Paulson et al, 2007). Relevant mutants from our previous work are shown in Figure 3b.…”

Section: Resultsmentioning

confidence: 99%

Transcriptional factor HBP1 targets P16INK4A, upregulating its expression and consequently is involved in Ras-induced premature senescence

Wang

Liu

et al. 2010

Oncogene

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Oncogene-mediated premature senescence has emerged as a potential tumor-suppressive mechanism in early cancer transitions. Many studies showed that Ras and p38 mitogen-activated protein kinase (MAPK) participate in premature senescence. Our previous work indicated that the HMG box-containing protein 1 (HBP1) transcription factor is involved in Ras-and p38 MAPK-induced premature senescence, but the mechanism of which has not yet been identified. Here, we showed that the p16 INK4A cyclin-dependent kinase inhibitor is a novel target of HBP1 participating in Ras-induced premature senescence. The promoter of the p16 INK4A gene contains an HBP1-binding site at position À426 to À433 bp from the transcriptional start site. HBP1 regulates the expression of the endogenous p16 INK4A gene through direct sequence-specific binding. With HBP1 expression and the subsequent increase of p16 INK4A gene expression, Ras induces premature senescence in primary cells. The data suggest a model in which Ras and p38 MAPK signaling engage HBP1 and p16 INK4A to trigger premature senescence. In addition, we report that HBP1 knockdown is also required for Ras-induced transformation. All the data indicate that the mechanism of HBP1-mediated transcriptional regulation is important for not only premature senescence but also tumorigenesis.

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Section: Resultsmentioning

confidence: 99%

Transcriptional factor HBP1 targets P16INK4A, upregulating its expression and consequently is involved in Ras-induced premature senescence

Wang

Liu

et al. 2010

Oncogene

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“…The 3D structure of eTAFH was elucidated by using a combination of manual and automatic nuclear Overhauser effect (NOE) assignment procedures ( Table 1, which is published as supporting information on the PNAS web site). The calculated 3D structure of eTAFH shows the conformation when interacting with HEB AD1 [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] . The ensemble of the 20 lowest-energy NMR structures shows four well defined ␣-helical regions (␣1-␣4) arranged in an unusual lefthanded, up-and-down four-helix bundle topology ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…The location of a binding interface at this position in eTAFH is a considerable divergence from the ␣1͞␣2 site used by PAH1 or PAH2 domains (Fig. 4 b and d) (15)(16)(17)26). However, both sites are characterized by a central hydrophobic cavity encircled by polar residues and are thus well suited for interactions with small amphiphatic ␣-helical motifs.…”

Section: Modeling Of the Tafh:ad1 12-28 Complexmentioning

confidence: 99%

“…3b). In pull-down assays using GST-HEB [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] fusions, mutations in eTAFH that suppress E protein silencing by ETO also inhibit AD1 binding (Fig. 3c), demonstrating a direct link between the eTAFH:AD1 interaction and E protein repression.…”

Section: Etafh Is Structurally Related To Sin3 Paired Amphiphatic Helmentioning

confidence: 99%

“…The 3D structure shows the conformation of eTAFH when interacting with a 17-residue peptide derived from the Nterminal AD of the human E protein HeLa E-box-binding protein (HEB) (AD1 [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] ). We establish by a thorough mutational analysis that eTAFH is the critical domain involved in E protein silencing by ETO and further demonstrate that point mutations of key conserved residues abrogates this interaction.…”

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confidence: 99%

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The acute myeloid leukemia fusion protein AML1-ETO targets E proteins via a paired amphipathic helix-like TBP-associated factor homology domain

Plevin

Zhang

Guo

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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Up to 15% of acute myeloid leukemias (AMLs) are characterized by the abnormal expression of the eight-twenty-one (ETO) transcriptional corepressor within an AML1-ETO fusion protein. The t(8;21) chromosomal translocation serves not only to disrupt WT AML1 function but also to introduce ETO activity during hematopoiesis. AML1-ETO was recently shown to inhibit E protein transactivation by physically displacing WT coactivator proteins in an interaction mediated by ETO. Here, we present the 3D solution structure of the human ETO TAFH (eTAFH) domain implicated in AML1-ETO:E protein interactions and report an unexpected fold similarity to paired amphipathic helix domains from the transcriptional corepressor Sin3. We identify and characterize a conserved surface on eTAFH that is essential for ETO:E protein recognition and show that the mutation of key conserved residues at this site alleviates ETObased silencing of E protein transactivation. Our results address uncharacterized aspects of the corepression mechanism of ETO and suggest that eTAFH may serve to recruit ETO (or AML1-ETO) to DNA-bound transcription factors. Together, these findings imply that a cofactor exchange mechanism, analogous to that described for E protein inhibition, may represent a common mode of action for ETO.corepressor ͉ NMR ͉ protein structure ͉ sin3 C ore binding factor (CBF) is an essential hematopoietic transcriptional regulator that is frequently mutated in acute myeloid leukemias (AMLs) (1, 2). In up to 15% of AML cases, a translocation between chromosomes 8 and 21 replaces a portion of the gene encoding the CBF subunit AML1 with a gene specifying an unrelated corepressor protein, eight-twenty-one (ETO) (3, 4). The subsequent fusion protein, AML1-ETO, contains the DNA-binding domain from AML1 fused to most of ETO. Expression of this chimeric protein and the consequent disruption of WT AML1 function are key events in the production of an AML phenotype (5). In WT cells CBF regulates chromatin remodeling of target genes by recruiting coactivators and histone acetyl transferases (6). In t(8;21) cells, the AML1-ETO fusion still binds CBF target DNA sequences through the AML1 DNA-binding domain; however, the ETO fusion partner functionally dominates by recruiting proteins involved in chromatin repression (e.g., corepressors and histone deacetylases) (1, 7). The formation of a corepressor complex involving AML1-ETO serves to shut down gene expression of genes normally activated by CBF.As an alternative or complementary mechanism involving distinct target genes, recent studies have shown that AML1-ETO can silence E protein transactivation (8). E proteins comprise a family of widely expressed transcription factors involved in regulating cell growth, differentiation, and apoptosis (9-11). DNA-bound E proteins interact with the histone acetyl transferase p300͞CREB binding protein, leading to histone modifications that facilitate transcription initiation (8, 12). However, AML1-ETO very strongly interacts with E proteins through an N-terminal activation...

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The neuronal transcription factor Myt1L interacts via a conserved motif with the PAH1 domain of Sin3 to recruit the Sin3L/Rpd3L histone deacetylase complex

Marcum

Radhakrishnan

2020

FEBS Letters

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The Sin3L/Rpd3L histone deacetylase (HDAC) complex is one of six major HDAC complexes in the nucleus, and its recruitment by promoter‐bound transcription factors is an important step in many gene transcription regulatory pathways. Here, we investigate how the Myt1L zinc finger transcription factor, important for neuronal differentiation and the maintenance of neuronal identity, recruits this complex at the molecular level. We show that Myt1L, through a highly conserved segment shared with its paralogs, interacts directly and specifically with the Sin3 PAH1 domain, binding principally to the canonical hydrophobic cleft found in paired amphipathic helix domain (PAH) domains. Our findings are relevant not only for other members of the Myt family but also for enhancing our understanding of the rules of protein–protein interactions involving Sin3 PAH domains.

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HBP1 and Mad1 repressors bind the Sin3 corepressor PAH2 domain with opposite helical orientations

Cited by 67 publications

References 49 publications

Transcriptional factor HBP1 targets P16INK4A, upregulating its expression and consequently is involved in Ras-induced premature senescence

Transcriptional factor HBP1 targets P16INK4A, upregulating its expression and consequently is involved in Ras-induced premature senescence

The acute myeloid leukemia fusion protein AML1-ETO targets E proteins via a paired amphipathic helix-like TBP-associated factor homology domain

The neuronal transcription factor Myt1L interacts via a conserved motif with the PAH1 domain of Sin3 to recruit the Sin3L/Rpd3L histone deacetylase complex

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