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Author

Tyler T. Hickman

Other affiliations: Tufts Medical Center, Tufts University, Harvard University  ...read more
Bio: Tyler T. Hickman is an academic researcher from Massachusetts Eye and Ear Infirmary. The author has contributed to research in topics: Stress granule & Cochlea. The author has an hindex of 11, co-authored 14 publications receiving 4813 citations. Previous affiliations of Tyler T. Hickman include Tufts Medical Center & Tufts University.

Papers
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Journal ArticleDOI
23 Dec 2010-Nature
TL;DR: A cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains is reported, establishing proof-of-concept for targeting protein–protein interactions of epigenetic ‘readers’, and providing a versatile chemical scaffold for the development of chemical probes more broadly throughout the b romodomain family.
Abstract: Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.

3,489 citations

Journal ArticleDOI
TL;DR: Stress granule condensation of translationally arrested mRNAs requires G3BP and requires its RGG region for SGC and for interactions with 40S ribosomal subunits.
Abstract: Mammalian stress granules (SGs) contain stalled translation preinitiation complexes that are assembled into discrete granules by specific RNA-binding proteins such as G3BP. We now show that cells lacking both G3BP1 and G3BP2 cannot form SGs in response to eukaryotic initiation factor 2α phosphorylation or eIF4A inhibition, but are still SG-competent when challenged with severe heat or osmotic stress. Rescue experiments using G3BP1 mutants show that phosphomimetic G3BP1-S149E fails to rescue SG formation, whereas G3BP1-F33W, a mutant unable to bind G3BP partner proteins Caprin1 or USP10, rescues SG formation. Caprin1/USP10 binding to G3BP is mutually exclusive: Caprin binding promotes, but USP10 binding inhibits, SG formation. G3BP interacts with 40S ribosomal subunits through its RGG motif, which is also required for G3BP-mediated SG formation. We propose that G3BP mediates the condensation of SGs by shifting between two different states that are controlled by the phosphorylation of S149 and by binding to Caprin1 or USP10.

438 citations

Journal ArticleDOI
TL;DR: It is shown that ANG inhibits protein synthesis and promotes arsenite- and pateamine A-induced assembly of stress granules (SGs) that are abrogated in cells transfected with the ANG inhibitor RNH1.

404 citations

Journal ArticleDOI
03 Apr 2008-Oncogene
TL;DR: Together, these data suggest that BRD–NUT fusion proteins contribute to carcinogenesis by associating with chromatin and interfering with epithelial differentiation.
Abstract: An unusual group of carcinomas, here termed nuclear protein in testis (NUT) midline carcinomas (NMC), are characterized by translocations that involve NUT, a novel gene on chromosome 15. In about 2/3rds of cases, NUT is fused to BRD4 on chromosome 19. Using a candidate gene approach, we identified two NMCs harboring novel rearrangements that result in the fusion of NUT to BRD3 on chromosome 9. The BRD3-NUT fusion gene encodes a protein composed of two tandem chromatin-binding bromodomains, an extra-terminal domain, a bipartite nuclear localization sequence, and almost the entirety of NUT that is highly homologous to BRD4-NUT. The function of NUT is unknown, but here we show that NUT contains nuclear localization and export sequences that promote nuclear-cytoplasmic shuttling via a leptomycin-sensitive pathway. In contrast, BRD3-NUT and BRD4-NUT are strictly nuclear, implying that the BRD moiety retains NUT in the nucleus via interactions with chromatin. Consistent with this idea, FRAP studies show that BRD4, BRD4-NUT and BRD3-NUT have significantly slower rates of lateral nuclear diffusion than that of NUT. To investigate the functional role of BRD-NUT fusion proteins in NMCs, we investigated the effects of siRNA-induced BRD3-NUT and BRD4-NUT withdrawal. Silencing of these proteins in NMC cell lines resulted in squamous differentiation and cell cycle arrest. Together, these data suggest that BRD-NUT fusion proteins contribute to carcinogenesis by associating with chromatin and interfering with epithelial differentiation.

386 citations

Journal ArticleDOI
TL;DR: The results suggest that O-GlcNAc modification of the translational machinery is required for aggregation of untranslated messenger ribonucleoproteins into SGs and the lack of enzymes of the hexosamine biosynthetic pathway in budding yeast may contribute to differences between mammalian SGs
Abstract: Stress granules (SGs) and processing bodies (PBs) are microscopically visible ribonucleoprotein granules that cooperatively regulate the translation and decay of messenger RNA 1–3 . Using an RNA-mediated interference-based screen, we identify 101 human genes required for SG assembly, 39 genes required for PB assembly, and 31 genes required for coordinate SG and PB assembly. Although 51 genes encode proteins involved in mRNA translation, splicing and transcription, most are not obviously associated with RNA metabolism. We find that several components of the hexosamine biosynthetic pathway, which reversibly modifies proteins with O-linked N-acetylglucosamine (O-GlcNAc) in response to stress, are required for SG and PB assembly. O-GlcNAc-modified proteins are prominent components of SGs but not PBs, and include RACK1 (receptor for activated C kinase 1), prohibitin-2, glyceraldehyde-3-phosphate dehydrogenase and numerous ribosomal proteins. Our results suggest that O-GlcNAc modification of the translational machinery is required for aggregation of untranslated messenger ribonucleoproteins into SGs. The lack of enzymes of the hexosamine biosynthetic pathway in budding yeast may contribute to differences between mammalian SGs and related yeast EGP (eIF4E, 4G and Pab1 containing) bodies.

360 citations


Cited by
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Journal ArticleDOI
23 Dec 2010-Nature
TL;DR: A cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains is reported, establishing proof-of-concept for targeting protein–protein interactions of epigenetic ‘readers’, and providing a versatile chemical scaffold for the development of chemical probes more broadly throughout the b romodomain family.
Abstract: Epigenetic proteins are intently pursued targets in ligand discovery. So far, successful efforts have been limited to chromatin modifying enzymes, or so-called epigenetic 'writers' and 'erasers'. Potent inhibitors of histone binding modules have not yet been described. Here we report a cell-permeable small molecule (JQ1) that binds competitively to acetyl-lysine recognition motifs, or bromodomains. High potency and specificity towards a subset of human bromodomains is explained by co-crystal structures with bromodomain and extra-terminal (BET) family member BRD4, revealing excellent shape complementarity with the acetyl-lysine binding cavity. Recurrent translocation of BRD4 is observed in a genetically-defined, incurable subtype of human squamous carcinoma. Competitive binding by JQ1 displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. These data establish proof-of-concept for targeting protein-protein interactions of epigenetic 'readers', and provide a versatile chemical scaffold for the development of chemical probes more broadly throughout the bromodomain family.

3,489 citations

Journal ArticleDOI
06 Jul 2012-Cell
TL;DR: The basic principles behind DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated targeting are presented and the evidence suggesting that their misregulation can culminate in cancer is highlighted.

2,501 citations

Journal ArticleDOI
TL;DR: Next-generation sequencing is providing a window for visualizing the human epigenome and how it is altered in cancer, including linking epigenetic abnormalities to mutations in genes that control DNA methylation, the packaging and the function of DNA in chromatin, and metabolism.
Abstract: The past decade has highlighted the central role of epigenetic processes in cancer causation, progression and treatment. Next-generation sequencing is providing a window for visualizing the human epigenome and how it is altered in cancer. This view provides many surprises, including linking epigenetic abnormalities to mutations in genes that control DNA methylation, the packaging and the function of DNA in chromatin, and metabolism. Epigenetic alterations are leading candidates for the development of specific markers for cancer detection, diagnosis and prognosis. The enzymatic processes that control the epigenome present new opportunities for deriving therapeutic strategies designed to reverse transcriptional abnormalities that are inherent to the cancer epigenome.

2,483 citations

Journal ArticleDOI
11 Apr 2013-Cell
TL;DR: This work investigates how inhibition of the widely expressed transcriptional coactivator BRD4 leads to selective inhibition ofThe MYC oncogene in multiple myeloma (MM), and finds that super-enhancers were found at key oncogenic drivers in many other tumor cells.

2,292 citations