Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.30.2 (endonuclease)
 18,621 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the association of the triiodothyronine (T3) nuclear receptor with rat liver chromatin by the use of selective endonuclease digestion and differential solubilization. The T3 receptor was found in a fraction of chromatin having some of the characteristics of active chromatin: (a) It is highly sensitive to DNase I and micrococcal nuclease digestion; (b) it is enriched in nonhistone proteins and depleted of histone (H-1). Micrococcal nuclease and pancreatic DNase I excised two receptor-containing fragments from chromatin, a minor (12--14 S) form and a major (5.5--6.0 S) form. The latter structure has a Stokes radius of 42 +/- 2 A and an estimated molecular weight of 95400 when a partial specific volume of 0.725 cm3/g for protein is used. It contains DNA but no histones. Similar receptor-containing fragments were excised from chromatin of other rat tissues, including brain, kidney, and heart. Both the 5.5--6 S and the 12--14 S receptor-containing chromatin structures are converted by 0.5 M KCl to the 3.5 S form (R0 35 A molecular weight 50500). Titration with micrococcal nuclease and pancreatic DNase I revealed that the 5.5--6 S form is preferentially excised by endonuclease. Neither receptor occupancy nor thyroidal status had an apparent effect on the susceptibility of chromatin to endonucleolytic digestion nor did they influence the distribution of T3 receptors in chromatin. Our results suggest that T3 receptors are not tightly associated with nucleosomes, the basic subunit of chromatin, but are associated with the DNA-linking nucleosomes in structurally modified regions of chromatin in rat liver nuclei. The T3 receptor-containing fragment may well represent a higher order of structural complexity necessary for T3 action at the cellular level.
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PMID:Association of the thyroid hormone receptor with rat liver chromatin. 627 79

Chromosomal translocations are a hallmark of leukemia/lymphoma and also appear in solid tumors, but the underlying mechanism remains elusive. By establishing a cellular model that mimics the relative frequency of authentic translocation events without proliferation selection, we report mechanisms of nuclear receptor-dependent tumor translocations. Intronic binding of liganded androgen receptor (AR) first juxtaposes translocation loci by triggering intra- and interchromosomal interactions. AR then promotes site-specific DNA double-stranded breaks (DSBs) at translocation loci by recruiting two types of enzymatic activities induced by genotoxic stress and liganded AR, including activation-induced cytidine deaminase and the LINE-1 repeat-encoded ORF2 endonuclease. These enzymes synergistically generate site-selective DSBs at juxtaposed translocation loci that are ligated by nonhomologous end joining pathway for specific translocations. Our data suggest that the confluence of two parallel pathways initiated by liganded nuclear receptor and genotoxic stress underlies nonrandom tumor translocations, which may function in many types of tumors and pathological processes.
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PMID:Nuclear receptor-induced chromosomal proximity and DNA breaks underlie specific translocations in cancer. 2000 97

Dysregulated gene expression resulting from abnormal epigenetic alterations including histone acetylation and deacetylation has been demonstrated to play an important role in driving tumor growth and progression. However, the mechanisms by which specific histone deacetylases (HDACs) regulate differentiation in solid tumors remains unclear. Using pediatric rhabdomyosarcoma (RMS) as a paradigm to elucidate the mechanism blocking differentiation in solid tumors, we identified HDAC3 as a major suppressor of myogenic differentiation from a high-efficiency Clustered regularly interspaced short palindromic repeats (CRISPR)-based phenotypic screen of class I and II HDAC genes. Detailed characterization of the HDAC3-knockout phenotype in vitro and in vivo using a tamoxifen-inducible CRISPR targeting strategy demonstrated that HDAC3 deacetylase activity and the formation of a functional complex with nuclear receptor corepressors (NCORs) were critical in restricting differentiation in RMS. The NCOR/HDAC3 complex specifically functions by blocking myoblast determination protein 1 (MYOD1)-mediated activation of myogenic differentiation. Interestingly, there was also a transient up-regulation of growth-promoting genes upon initial HDAC3 targeting, revealing a unique cancer-specific response to the forced transition from a neoplastic state to terminal differentiation. Our study applied modifications of CRISPR/CRISPR-associated endonuclease 9 (Cas9) technology to interrogate the function of essential cancer genes and pathways and has provided insights into cancer cell adaptation in response to altered differentiation status. Because current pan-HDAC inhibitors have shown disappointing results in clinical trials of solid tumors, therapeutic targets specific to HDAC3 function represent a promising option for differentiation therapy in malignant tumors with dysregulated HDAC3 activity.
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PMID:CRISPR screen identifies the NCOR/HDAC3 complex as a major suppressor of differentiation in rhabdomyosarcoma. 2795 29