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PubMed2005

The condensin I subunit Barren/CAP-H is essential for the structural integrity of centromeric heterochromatin during mitosis.

During cell division, chromatin undergoes structural changes essential to ensure faithful segregation of the genome. Condensins, abundant components of mitotic chromosomes, are known to form two different complexes, condensins I and II. To further examine the role of condensin I in chromosome structure and in particular in centromere organization, we depleted from S2 cells the Drosophila CAP-H homologue Barren, a subunit exclusively associated with condensin I. In the absence of Barren/CAP-H the condensin core subunits DmSMC4/2 still associate with chromatin, while the other condensin I non-structural maintenance of chromosomes family proteins do not. Immunofluorescence and in vivo analysis of Barren/CAP-H-depleted cells showed that mitotic chromosomes are able to condense but fail to resolve sister chromatids. Additionally, Barren/CAP-H-depleted cells show chromosome congression defects that do not appear to be due to abnormal kinetochore-microtubule interaction. Instead, the centromeric and pericentromeric heterochromatin of Barren/CAP-H-depleted chromosomes shows structural problems. After bipolar attachment, the centromeric heterochromatin organized in the absence of Barren/CAP-H cannot withstand the forces exerted by the mitotic spindle and undergoes irreversible distortion. Taken together, our data suggest that the condensin I complex is required not only to promote sister chromatid resolution but also to maintain the structural integrity of centromeric heterochromatin during mitosis.

Adenosine Triphosphatases↗
PubMed1997

Designing of plant artificial chromosome (PAC) by using the Chlorella smallest chromosome as a model system.

As a model for plant-type chromosomes, we have been characterizing molecular organization of the Chlorella vulgaris C-169 chromosome I. To identify chromosome structural elements including the centromeric region and replication origins, we constructed a chromosome I specific cosmid library and aligned each cosmid clones to generate contigs. So far, more than 80% of the entire chromosome I has been covered. A complete clonal physical reconstitution of chromosome I provides information on the structure and genomic organization of plant genome. We propose our strategy to construct an artificial chromosome by assembling the functional chromosome structural elements identified on Chrorella chromosome I.

Centromere↗
PubMed1997

PA28 subunits of the mouse proteasome: primary structures and chromosomal localization of the genes.

The 20S proteasome is a multi-subunit protease responsible for the production of peptides presented by major histocompatibility complex (MHC) class I molecules. Recent evidence indicates that an interferon-gamma (IFN-gamma)-inducible PA28 activator complex enhances the generation of class I binding peptides by altering the cleavage pattern of the proteasome. In the present study, we determined the primary structures of the mouse PA28 alpha- and beta-subunits. The deduced amino acid sequences of the alpha- and beta-subunits were 49% identical. We also determined the primary structure of the mouse PA28 gamma-subunit (Ki antigen), a protein of unknown function structurally related to the alpha- and beta-subunits. The amino acid sequence identity of the gamma-subunit to the alpha- and beta-subunits was 40% and 32%, respectively. Interspecific backcross mapping showed that the mouse genes coding for the alpha- and beta-subunits (designated Psme1 and Psme2, respectively) are tightly linked and map close to the Atp5g1 locus on chromosome 14. Thus, unlike the LMP2 and LMP7 subunits, the IFN-gamma-inducible subunits of PA28 are encoded outside the MHC. The gene coding for the gamma-subunit (designated Psme3) was mapped to the vicinity of the Brca1 locus on chromosome 11. A computer search of the DNA databases identified a gamma-subunit-like protein in ticks and Caenorhabditis elegans, the organisms with no adaptive immune system. It appears that the IFN-gamma-inducible alpha- and beta-subunits emerged by gene duplication from a gamma-subunit-like precursor.

Amino Acid Sequence↗
PubMed1998

Genetic aberrations in hypodiploid breast cancer: frequent loss of chromosome 4 and amplification of cyclin D1 oncogene.

The evolution of somatic genetic aberrations in breast cancer has remained poorly understood. The most common chromosomal abnormality is hyperdiploidy, which is thought to arise via a transient hypodiploid state. However, hypodiploidy persists in 1 to 2% of breast tumors, which are characterized by a poor prognosis. We studied the genetic aberrations in 15 flow cytometrically hypodiploid breast cancers by comparative genomic hybridization (CGH) and fluorescence in situ hybridization (FISH). Surprisingly, numerous copy number gains were detected in addition to the copy number losses. The number of gains per tumor was 4.3 +/- 3.2 and that of losses was 4.5 +/- 3.3 (mean +/- SD), which is similar to that previously observed in hyperdiploid breast cancers. Gains at chromosomes or chromosomal regions at 11q13, 1q, 19, and 16p and losses of 2q, 4, 6q, 9p, 13, and 18 were most commonly observed. Compared with unselected breast carcinomas, hypodiploid tumors showed certain differences. Loss of chromosome 4 (53%) and gain of 11q13 (60%) were significantly more common in hypodiploid tumors. The gain at 11q13 was found by FISH to harbor amplification of the Cyclin D1 oncogene, which is therefore three to four times more common in hypodiploid than in unselected breast cancers (15 to 20%). Structural chromosomal aberrations (such as Cyclin D1 amplification) were present both in diploid and hypodiploid tumor cell populations, as assessed by FISH and CGH after flow cytometric sorting. Together these results indicate that hypodiploid tumors form a distinct genetic entity of invasive breast cancer, although they probably share a common genetic evolution pathway where structural chromosomal aberrations precede gross DNA ploidy changes.

Adult↗
PubMed2000

Structure and chromosomal localization of the human and mouse muscle fructose-1,6-bisphosphatase genes.

Mammalian skeletal muscle contains fructose-1,6-bisphosphatase (Fru-1,6-P(2)ase), a key enzyme of glyconeogenesis. We have shown previously that muscle Fru-1,6-P(2)ase is encoded by a gene different from that coding for the liver isoenzyme. Starting with genomic YAC libraries and based on the cDNA sequences of human and mouse muscle Fru-1,6-P(2)ases together with the known gene structures of two mammalian liver fructose-1,6-bisphosphatases, we have PCR-amplified and sequenced all functional parts of the human and mouse muscle fructose-1,6-bisphosphatase genes and determined their chromosomal localization. The human gene (FBP2), localized at chromosome 1p36.1-2, spans about 30 kb, while the mouse gene (Fbp2) at chromosome 13B3-C1 is more compact (about 21 kb). Intron lengths are only poorly conserved between the two genes, while intron number and positions are identical in all hitherto analyzed mammalian fructose-1,6-bisphosphatase isoenzyme genes. Transcriptional start sites were found to be located 97 and 95bp before the start codon in the human gene and 35 bp before the start codon in the mouse homolog. A comparison of the 5'-flanking sequences of the two genes revealed a 56% homology up to human bp -607 before the first transcriptional start point, while upstream of this region we found no similarity. The data presented in this paper provide a basis for further studies of the mechanism of expression regulation and the elucidation of the physiological role of the enzyme.

Animals↗
PubMed1997

The mouse genes encoding the third pair of beta-type proteasome subunits regulated reciprocally by IFN-gamma: structural comparison, chromosomal localization, and analysis of the promoter.

Proteasomes are the multisubunit protease involved in the generation of peptides presented by MHC class I molecules. When cells are stimulated with IFN-gamma, two MHC-encoded subunits, low Mr polypeptide 2 (LMP2) and LMP7, are incorporated into the proteasomal complex by displacing the housekeeping subunits, designated Y and X, respectively. Recent evidence indicates that besides the LMP2/Y and LMP7/X subunits, there is another pair of structurally similar beta-type subunits, designated MECL1 and Z, whose expression is regulated reciprocally by IFN-y. In the present study we determined the genomic organizations of the mouse genes, Psmb10 and Psmb7, that encode the MECL1 and Z subunits, respectively. Although the two genes differ > 10-fold in size, they both have eight exons, with the exon-intron boundaries located precisely at the equivalent positions. The organization of the Psmb10 and Psmb7 genes differs from those of the genes encoding the other two pairs of IFN-gamma-regulated subunits. Thus, comparison of the gene structures supports the idea that Psmb10 and Psmb7 arose by duplication from an immediate common ancestor. The promoter region of the Psmb10 gene contains two IFN-stimulated response elements, the functionality of which was confirmed by in vitro mutagenesis. The mouse Psmb10 gene maps to chromosome 8, thus outside the MHC like its human counterpart. Besides the Psmb7 gene previously mapped to chromosome 2, a truncated processed pseudogene, designated Psmb7-ps, was identified and mapped to chromosome X.

Amino Acid Sequence↗
PubMed1993

Structure and chromosomal localization of the human constitutive endothelial nitric oxide synthase gene.

Endothelial nitric oxide (NO) synthase is a unique NO synthase isoform that is expressed constitutively by vascular endothelium both in vivo and in vitro and is believed essential to local vascular homeostasis. This calcium/calmodulin-dependent isoform is distinct from neuronal NO synthase. Genomic clones encoding the human endothelial NO synthase were isolated and the structural organization of the gene was determined. The gene contains 26 exons spanning approximately 21 kilobases of genomic DNA, encodes a messenger RNA of 4052 nucleotides, and is present as a single copy in the haploid human genome. Characterization of 5'-flanking genomic regions indicates that the endothelial NO synthase promoter is "TATA-less" and exhibits proximal promoter elements consistent with a constitutively expressed gene that is found in endothelial cells, namely Sp1 and GATA motifs. The 5'-flanking region contains putative AP-1, AP-2, NF-1, heavy metal, acute-phase response shear stress, and sterol-regulatory cis-elements. The human endothelial NO synthase gene was assigned to the 7q35-->7q36 region of chromosome 7 by Southern blot hybridization of human-rodent somatic cell hybrid lines and fluorescence in situ hybridization, whereas human neuronal NO synthase localized to the 12q24.2 region of chromosome 12.

Amino Acid Oxidoreductases↗
PubMed1991

Structure and chromosomal localization of DNA sequences related to ribosomal subrepeats in Vicia faba.

Subrepeating sequences of 325 bp found in the ribosomal intergenic spacer (IGS) of Vicia faba and responsible for variations in the length of the polycistronic units for rRNA were isolated and used as probes for in situ hybridization. Hybridization occurs at many regions of the metaphase chromosomes besides those bearing rRNA genes, namely chromosome ends and all the heterochromatic regions revealed by enhanced fluorescence after quinacrine staining. The DNA homologous to the 325 bp repeats that does not reside in the IGS was isolated, cloned and sequenced. It is composed of tandemly arranged 336 bp elements, each comprising two highly related 168 bp sequences. This structure is very similar to that of the IGS repeats and ca. 75% nucleotide sequence identity can be observed between these and the 168 bp doublets. The most obvious difference lies in the deletion, in the former, of a 14 bp segment from one of the two related sequences. It is hypothesized that the IGS repeats are derived from the 336 bp elements and have been transposed to ribosomal cistrons from other genome fractions. The possible relations between these sequences and others with similar structural features found in other species are discussed.

Base Sequence↗
PubMed1997

Structure and chromosomal localization of the beta2 subunit of the human brain sodium channel.

The beta2 subunit of rat brain voltage-gated sodium channels modulates their cell-surface expression and gating. It is a 33 kDa glycoprotein with a single transmembrane segment and an immunoglobulin-like fold resembling those of cell adhesion molecules in the extracellular domain. Here we report the cDNA sequence and genomic localization of the gene encoding the human beta2 subunit. The mature human beta2 protein has 89% amino acid sequence identity to rat beta2 and has four conserved consensus sites for N-linked glycosylation. The extracellular cysteine residues which are predicted to form the disulfide linkage in the immunoglobulin-like fold are also conserved, indicating that the overall structure is preserved between these two species. Using fluorescent in situ hybridization (FISH), we localized the beta2 gene to human chromosome 11q3. Mutations in this region of chromosome 11 in Charcot-Marie-Tooth syndrome type 4B and in other neurological diseases cause abnormal myelination and neurological deficits. The similarity of beta2 to cell adhesion molecules, including myelin protein p0, and its chromosomal location at 11q23 suggest a potential role in these demyelinating diseases.

Amino Acid Sequence↗
PubMed2003

In vivo requirements for rDNA chromosome condensation reveal two cell-cycle-regulated pathways for mitotic chromosome folding.

Chromosome condensation plays an essential role in the maintenance of genetic integrity. Using genetic, cell biological, and biochemical approaches, we distinguish two cell-cycle-regulated pathways for chromosome condensation in budding yeast. From G(2) to metaphase, we show that the condensation of the approximately 1-Mb rDNA array is a multistep process, and describe condensin-dependent clustering, alignment, and resolution steps in chromosome folding. We functionally define a further postmetaphase chromosome assembly maturation step that is required for the maintenance of chromosome structural integrity during segregation. This late step in condensation requires the conserved mitotic kinase Ipl1/aurora in addition to condensin, but is independent of cohesin. Consistent with this, the late condensation pathway is initiated during the metaphase-to-anaphase transition, supports de novo condensation in cohesin mutants, and correlates with the Ipl1/aurora-dependent phosphorylation of condensin. These data provide insight into the molecular mechanisms of higher-order chromosome folding and suggest that two distinct condensation pathways, one involving cohesins and the other Ipl1/aurora, are required to modulate chromosome structure during mitosis.

Adenosine Triphosphatases↗
PubMed1998

Genomic structures and chromosomal location of p91, a novel murine regulatory receptor family.

Recently, we found a novel murine cell-surface glycoprotein, designated as p91, expressed mainly in myeloid cells such as macrophages and mast cells. The molecule has six immunoglobulin-like extracellular domains, a transmembrane segment, and a cytoplasmic tail containing four immunoreceptor tyrosine-based inhibition motif (ITIM) or ITIM-like sequences, resembling the structural features of human killer-cell inhibitory receptors (KIR). Here we show that p91 comprises a polymorphic gene family, harboring one potent inhibitory-type p91 and at least two other p91 genes. Tyrosine-phosphorylated, but not nonphosphorylated, synthetic peptides matching the third ITIM and the fourth ITIM-like sequences, respectively, found in the cytoplasmic portion of p91A, the sole inhibitory-type p91, were associated with the tyrosine phosphatases, SHP-1 and SHP-2. In addition, the phosphotyrosyl peptide matching the third ITIM sequence also bound the inositol 5-phosphatase, SHIP. These results support the notion that p91A may function as an inhibitory cell-surface molecule against cell activation. The p91 genes were shown to be clustered in the proximal region of mouse chromosome 7, a syntenic position of human chromosome 19 where the genes for the KIR family are found. A human cDNA clone cross-hybridizing to a murine p91 probe was isolated from a human spleen cDNA library, and was found to code for a molecule quite similar to members of the immunoglobulin-like transcript (or ILT) family. The gene was found to be located on human chromosome 19q13.3-13.4. These results establish the existence of a novel set of potent regulatory receptors in mouse and man, similar but different from the KIR family.

Amino Acid Sequence↗
PubMed2000

Genetic characterization of immortalized human prostate epithelial cell cultures. Evidence for structural rearrangements of chromosome 8 and i(8q) chromosome formation in primary tumor-derived cells.

We have utilized a combination of conventional and spectral karyotyping (SKY) techniques and allelotype analysis to assess numerical and structural chromosome alterations in two cell lines derived from normal human prostatic epithelium, and three cell lines derived from human prostate primary tumor epithelium, immortalized with the E6 and E7 transforming genes of human papilloma virus (HPV) 16 or the large T-antigen gene of simian virus 40 (SV40). These studies revealed trisomy for chromosome 20 and rearrangements involving chromosomes 3, 4, 8, 9, 10, 16, 17, 18, 19, 21, or 22. In addition, the four HPV-immortalized cell lines exhibited extensive duplications or translocations involving the 11q chromosomal region. Interestingly, allelotyping data disclosed loss of 8p sequences in two of the three primary tumor-derived cell lines, and SKY data revealed that the loss of 8p sequences was directly due to i(8q) chromosome formation and/or other structural alterations of chromosome 8. This provides intriguing evidence that 8p loss in primary human prostate tumors may, in some cases, result from complex structural rearrangements involving chromosome 8. Moreover, the data reported here provide direct evidence that such complex structural rearrangements sometimes include i(8q) chromosome formation.

Cell Line, Transformed↗
PubMed1993

Structures and chromosomal localizations of two rat genes encoding S-adenosylmethionine decarboxylase.

S-Adenosylmethionine decarboxylase (AdoMetDC) is a ubiquitous enzyme in eukaryotic cells and responds to a wide variety of stimuli affecting growth. To provide a framework for understanding the molecular basis of the mechanisms responsible for regulating the expression of this enzyme activity, we recently cloned and sequenced the rat gene for AdoMetDC. Now we have isolated another, slightly different AdoMetDC gene from a rat genomic library. Comparison of the two genes shows a high degree of conservation of sequence and structural organization. The two genes share the following characteristics: (1) both are approximately 16 kb in size, have identical exon/intron boundaries, and exhibit similar intron/exon structural organization; and (2) the nucleotide sequences are highly conserved in the coding regions and in many introns. Analysis of mouse-rat somatic cell hybrids has localized both rat genes to chromosome 20. The most interesting feature of these genes is that their 5' flanking regions are totally different. The promoter activities of the 5' regulatory regions were assessed by transient gene expression assays in Rat-2 cells after fusion to the chloramphenicol acetyltransferase gene. Transient transfections with the chimeric DNAs demonstrated that these fragments were able to function as efficient promoters, indicating that the diverging 5' regions of two AdoMetDC genes contain functional, but different, regulatory transcription elements.

Adenosylmethionine Decarboxylase↗
PubMed1981

N-Acetoxy-acetylaminofluorene reacts preferentially with a control region of intracellular SV40 chromosome.

Many chemical carcinogens or their metabolites react with DNA; thus it is of interest to determine what effect chromosomal structure has on these reactions. The chromosome of simian virus 40 (SV40) is well suited for such studies; like chromatin of eukaryotic cells, it is organized into nucleosomes. The nucleotide sequence of SV40 is known, together with much about the pattern of viral gene expression and DNA replication, and the structure of the viral chromosome. We have investigated the binding of the ultimate carcinogen, N-acetoxy-acetylaminofluorene (AAAF), to specific regions of the SV40 chromosome in situ in the intact infected cell. The results, reported here, indicate that a region containing regulatory functions on the intracellular SV40 chromosome has unique structural properties which render it more susceptible to attack by AAAF than the rest of the SV40 genome. The preferential binding of AAAF to regulatory regions of chromatin may have implications for the mechanism of action of this and similar carcinogens.

2-Acetylaminofluorene↗
PubMed2000

Genomic structure and chromosomal localization of the gene encoding TRAX, a Translin-associated factor X.

The TRAX gene encodes a Translin-associated 33-kDa protein partner, TRAX. The TRAX protein has extensive amino acid homology with Translin, and contains bipartite nuclear targeting sequences, suggesting a possible role in the selective nuclear transport of Translin lacking any nuclear targeting motifs. In the present study, genomic clones of the human TRAX gene were isolated to determine the complete genomic organization. The genomic structure of the human TRAX gene was similar to that of the human Translin gene, consisting of six exons and five introns, encompassing approximately 27kb in genomic DNA. Northern blot analysis revealed a predominant transcript of approximately 2.7kb, and its distribution in various tissues was like that of Translin. Chromosomal mapping by fluorescence in situ hybridization (FISH) analysis allowed localization of the TRAX gene to human chromosome lq41.

Carrier Proteins↗
PubMed1997

Structure and chromosomal assignment of the human cathepsin K gene.

Cathepsin K is a recently identified lysosomal cysteine proteinase that is the major protease responsible for bone resorption and remodeling. Mutations in this gene cause the sclerosing osteochondrodysplasia pycnodysostosis. To assess its evolutionary relatedness to other cysteine proteases and to facilitate mutation identification in patients with pycnodysostosis, a genomic clone, 74e16, containing the cathepsin K gene was isolated from a human PAC library, and the cathepsin K genomic structure was determined. The cathepsin K gene contained eight exons and spanned approximately 9 kb. The transcription initiation site, determined by primer extension analysis, was 169 nucleotides upstream from the translation initiation site. The 5'-flanking region lacked a TATA box but contained two AP1 sites. Comparison of genomic and cDNA sequences suggested that this flanking sequence may be the major promoter in osteoclasts and macrophages. Cathepsin K was mapped to chromosome 1q21 by fluorescence in situ hybridization and found to reside within 150 kb of an evolutionarily related cysteine protease, cathepsin S. These findings expand our understanding of the papain family lysosomal cysteine proteases and should facilitate mutation analysis in pycnodysostosis.

Base Sequence↗
PubMed2002

Mouse pelota gene (Pelo): cDNA cloning, genomic structure, and chromosomal localization.

The pelota gene of Drosophila melanogaster encodes a protein which is included in cell cycle regulation. Mutations were found to result in spermatogenic arrest, female sterility and disturbances in the patterning of the eye. We have recently isolated and characterized cDNA clones coding for the human pelota gene (PELO). Here we describe the cloning of the murine pelota cDNA and gene (Pelo) that encodes a 385-amino-acid protein. The exon-intron structure of the gene, which contains three exons, was determined. Comparison of the mouse amino acid sequences with the human and Drosophila sequences revealed an overall high identity (96% and 70%, respectively). Northern blot analysis detected a 1.7-kb transcript in all tissues studied. Southern blot analyses revealed that the pelota gene is present as a single copy in the mouse genome. The mouse pelota gene (Pelo) was mapped to the distal end of chromosome 13, in a region that is homologous with a segment of human chromosome 5q11 containing the orthologous human gene. Cloning of the mouse gene is an important step to study the function of the pelota gene in mammals and to create a mouse model for this evolutionarily conserved gene.

Amino Acid Sequence↗
PubMed1996

Gene structure and chromosomal localization of the mouse NMDA receptor channel subunits.

Multiple espilon subunits are major determinants of the diversity of the N-methyl-D-aspartate (NMDA) receptor channel. The four epsilon subunit mRNAs exhibit distinct expression patterns in the brain. In an attempt to elucidate the molecular basis of selective and characteristic expression of the NMDA receptor channel subunits, we have isolated the gene encoding the mouse NMDA receptor epsilon 3 subunit and have determined its structural organization. The epsilon 3 subunit gene spans 17.5 kb and consists of 14 exons. The major transcription start site is 439 bp upstream of the ATG initiation codon as determined by primer extension and S1 nucleas protection analyses. Two polyadenylation sites are 397 (or 398) and 402 bp downstream of the termination codon. The 5'-flanking region of the epsilon 3 subunit gene contains GC-rich segments including consensus sequences for binding of the transcription factors Spl and EGR-1. The murine chromosomal locations of the five NMDA receptor channel subunits, the epsilon 1 (Grin2a), epsilon 2 (Grin2b), epsilon 3 (Grin2c), epsilon 4 (Grin2d) and zeta 1 (Grinl) subunits, were determined using an interspecific backcross mapping panel derived from crosses of [(C57BL/6JxM. spretus) F1xC57BL/6J] mice. Each of these genes mapped to a single chromosome location. The mapping results assigned the five loci to five different mouse autosomes, indicating that they have become well dispersed among mouse chromosomes.

Amino Acid Sequence↗