Compartmentalization within the nucleus: discovery of a novel subnuclear region.

Saunders, William S.; Cooke, Carol; Earnshaw, William C.

doi:10.1083/jcb.115.4.919

Cited by 60 publications

(33 citation statements)

References 39 publications

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“…Consistent with the independent results of Ascoli and Maul (2), the ND domains do not correspond to the nucleolus, kinetochores, or splicing centers. The ND antigens are also distinct in both molecular weight and subnuclear distribution from the polymorphic interphase karyosomal association antigens (42). The NDs do not correspond to coiled bodies; double (31) (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Some of these activities are carried out in distinct regions of the nucleus; ribosome biogenesis occurs within the nucleolus (13), splicing complexes are organized into splicing domains (14,17), and DNA replication occurs at discrete sites (15). Other less well-characterized regions of the nucleus have also been described, including nuclear bodies, which appear as granular fibrils defining the space between perichromatin and perinuclear chromatin (7,52), and polymorphic interphase karyosomal associations, which appear as nuclear domains that are very heterogeneous in size and number from one cell to the next (42). To what extent other morphological domains exist in the nucleus and whether they carry out distinct cellular functions are not known.…”

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confidence: 99%

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Nuclear dot antigens may specify transcriptional domains in the nucleus.

Xie¹,

Lambie²,

Snyder³

1993

Mol. Cell. Biol.

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A bank of 892 human autoimmune serum samples was screened by indirect immunofluorescence on human tissue culture A wide variety of cellular processes occur within the nucleus, including DNA replication, RNA transcription and processing, and ribosome biogenesis (18,33). Some of these activities are carried out in distinct regions of the nucleus; ribosome biogenesis occurs within the nucleolus (13), splicing complexes are organized into splicing domains (14, 17), and DNA replication occurs at discrete sites (15). Other less well-characterized regions of the nucleus have also been described, including nuclear bodies, which appear as granular fibrils defining the space between perichromatin and perinuclear chromatin (7, 52), and polymorphic interphase karyosomal associations, which appear as nuclear domains that are very heterogeneous in size and number from one cell to the next (42). To what extent other morphological domains exist in the nucleus and whether they carry out distinct cellular functions are not known.One method to determine whether specific subcellular domains exist within the mammalian nucleus is to screen sera from autoimmune disease patients for antibodies that recognize novel staining patterns. Patients with specific autoimmune diseases often contain antibodies directed to nuclear components (10,27,51). These include antibodies directed to kinetochores (5, 12, 20, 32), nuclear lamins (24, 37), topoisomerase I (29), proliferating-cell nuclear antigen (4,28,36), and splicing components (26,34,38). One unusual type of autoantibody recognizes speckled dots or nuclear dots (NDs) (2, 6, 39), which are visible as approximately six brightly staining dots in the nucleus.In this report, we describe autoantibodies directed to a 72,000-Mr ND antigen. The ND domain is distinct from known nuclear domains such as splicing centers or kinetochores. Cloning and molecular characterization of a major ND antigen are also reported. In the course of our studies, * Corresponding author. reports from two other laboratories have partially described ND antigens (2, 50). Our results indicate that the 72-kDa ND antigen is associated with nuclear DNA and can serve as a transcriptional activator in Saccharomyces cerevisiae and mammalian cells. MATERIALS AND METHODSStrains and sera. Human autoimmune sera were provided by J. Hardin and J. Craft of the Yale University School of Medicine and screened as described by Yang et al. (56

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Nuclear dot antigens may specify transcriptional domains in the nucleus.

Xie¹,

Lambie²,

Snyder³

1993

Mol. Cell. Biol.

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“…regulated by their association with particular sites or structures within the nucleus. Immunofluorescence has been used to describe compartmentalization of nuclear proteins of unknown function into novel focal structures (e.g., PML [16,79]; polymorphic interphase karyosomal association [PIKA] [65]) and has provided evidence that diverse processes, including DNA replication (27), RNA splicing (20), and DNA repair (23,48,58,76), may be compartmentalized within the nucleus. This experimental approach has also uncovered previously unsuspected roles for certain proteins, such as BRCA1, ATM, and ATR, in meiosis (36,69).…”

Section: Discussionmentioning

confidence: 99%

hMre11 and hRad50 Nuclear Foci Are Induced During the Normal Cellular Response to DNA Double-Strand Breaks †

Maser

Monsen

Nelms

et al. 1997

Molecular and Cellular Biology

466

342

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We previously identified a conserved multiprotein complex that includes hMre11 and hRad50. In this study, we used immunofluorescence to investigate the role of this complex in DNA double-strand break (DSB) repair. hMre11 and hRad50 form discrete nuclear foci in response to treatment with DSB-inducing agents but not in response to UV irradiation. hMre11 and hRad50 foci colocalize after treatment with ionizing radiation and are distinct from those of the DSB repair protein, hRad51. Our data indicate that an irradiated cell is competent to form either hMre11-hRad50 foci or hRad51 foci, but not both. The multiplicity of hMre11 and hRad50 foci is much higher in the DSB repair-deficient cell line 180BR than in repair-proficient cells. hMre11-hRad50 focus formation is markedly reduced in cells derived from ataxia-telangiectasia patients, whereas hRad51 focus formation is markedly increased. These experiments support genetic evidence from Saccharomyces cerevisiae indicating that Mre11-Rad50 have roles distinct from that of Rad51 in DSB repair. Further, these data indicate that hMre11-hRad50 foci form in response to DNA DSBs and are dependent upon a DNA damage-induced signaling pathway.Certain intrinsic programs in eukaryotic organisms, such as meiotic and mitotic recombination, mating type switching, and assembly of antigen receptor genes, involve the generation of DNA double-strand breaks (DSBs) (63,73,78). DNA DSBs are also caused by a variety of extrinsic factors, including exposure to ionizing radiation and genotoxic chemicals (19). Proteins that mediate DNA DSB repair are required for both intrinsic DNA recombination processes and the repair of extrinsically induced DNA damage. Thus, DSB repair deficiency results in sensitivity to DNA DSB-inducing agents and impairs meiotic and mitotic DNA recombination processes (21, 59). In addition, the failure to repair DNA DSBs can lead to the loss of genetic information by mutation, chromosome loss, or rearrangement and, in some instances, to cell death (29, 51).In both Saccharomyces cerevisiae and mammalian cells, recombinational repair of DSBs occurs either by homologous recombination or by nonhomologous end joining (9,24,50,64,68). The RAD52 epistasis group (RAD50-RAD57, RAD59, MRE11, and XRS2) is largely responsible for DSB repair in yeast (1,5,21,30). Mutations in these genes cause profound recombination defects as well as sensitivity to DSB-inducing agents. The RAD52 epistasis group can be subdivided into two subgroups according to specific functions in meiotic and mitotic recombination. In mitotic cells, S. cerevisiae RAD51 (ScRAD51), ScRAD52, ScRAD54, ScRAD55, and ScRAD57 comprise one subgroup, which mediates homologous recombination (21), whereas ScRAD50, ScMRE11, and ScXRS2 mediate nonhomologous end joining (50,68,77).We recently reported the identification of the human MRE11 and RAD50 homologs (15, 60). Mammalian homologs have also been identified for RAD51, RAD52, and RAD54 (7,34,71,72). Sequence homology between the yeast and human RAD52 epistasis group proteins,...

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“…We have shown that Bmil, Mphl/Rae-28, and M33 do not colocalize with splicing factors. Other less well-characterized nuclear substructures, which are more reminiscent of the Bmil, Mphl/Rae-28, and M33 distribution, have been described using a variety of human autoimmune antisera (Saunders et al 1991) and monoclonal antibodies. Some of the autoimmune sera detect proteins in interphase nuclei that colocalize with the RING finger protein PML.…”

Section: Are Constituents Of a Mammalian Pc Complexmentioning

confidence: 99%