This Week in Science

Science  26 Jul 2002:
Vol. 297, Issue 5581, pp. 473
  1. In Brevia

    A carefully controlled replication by Wright and Czeisler (p. 571; see the news story by Barinaga) of results previously reported in Science show that light exposure to the back of the knees does not in fact phase-shift the human circadian clock.

  2. Protons Passing Through Water

    In solution, a certain fraction of water molecules are dissociated into H3O+ and OH, and these species show much greater mobility than would be expected, based on comparisons to other ions. Spectroscopic studies of a mixture of HDO and D2O by Bakker and Nienhuys (p. 587) suggest an explanation—that the O-H stretch vibrations in liquid water are highly anharmonic. The addition of hydrogen-bonding interactions stretches the potential energy surface and decreases the level spacing. In the second vibrational excited state, which is at an energy that is only 20% of the dissociation energy of the O-H bond, the proton is already highly delocalized.

  3. Glowing Individuals

    Single-walled carbon nanotubes with different diameters and chiralities are different molecules with their own individual properties, but studying these differences requires methods for separating and stabilizing the nanotubes from bundles and ropes in which they form. O'Connell et al. (p. 593) used aggressive sonication and sodium dodecyl sulfate (SDS) to stabilize individual tubes, which they are then able to purify using centrifugation. The semiconducting nanotubes, upon being freed from quenching interactions with metallic nanotubes, display band-gap fluorescence at wavelengths between 800 and 1600 nanometers. This emission can be quenched when the nanotube side walls are protonated under acid conditions.

    CREDIT: O'CONNELL ET AL.
  4. Milky Way Interlopers

    The globular clusters of old stars that populate the halo of the Milky Way Galaxy are thought to represent the oldest objects left over from the initial collapse of the proto-Galaxy. Oddly, the clusters form two groups with slightly different ages and other properties. Yoon and Lee (p. 578; see the Perspective by Clement) have found a planar alignment of the metal-poor group of clusters in the outer halo. They suggest that these clusters are interlopers from a satellite galaxy that formed just before the Milky Way but that did not retreat fast enough to retain these few stray clusters.

  5. Monsoon Wetting

    Variations in monsoon activity are an important but poorly understood aspect of global weather patterns. Anderson et al. (p. 596; see the Perspective by Black) analyzed the relative abundance of Globigerina bulloides, a surface-dwelling species of foraminifera that is a particularly good proxy for upwelling conditions like those produced by strong monsoonal winds, in order to reconstruct the intensity of the Southwest Asian monsoon during the past millennium. This record from the Northwest Arabian Sea chronicles an increase in monsoon strength during the past four centuries, from a minimum around 1600 A.D. to the highest values of the entire interval at present. Their results suggest that the Southwest Asian monsoon intensities will continue to increase in strength if Northern Hemisphere temperatures continue to rise.

  6. Keeping the Forks on the Road

    Any failure in the many steps of DNA replication can result in the loss of chromosome integrity through the introduction of double-stranded (ds) DNA breaks (see the Viewpoint by Carr). Two reports focus on replication fork progression. To determine how replication forks are monitored, Sogo et al. (p. 599; see the cover) directly visualized the structure of replication forks in wild-type and checkpoint defective yeast cells using electron microscopy. In wild-type cells, stalled replication forks expose short regions of single-stranded (ss) DNA. In checkpoint defective cells, replication intermediates with long ssDNA regions and reversed forks are found, suggesting that dsDNA breaks arise through inappropriate processing of the backed-up forks. The ATR/ATM family of chromosome-bound signal transduction proteins, which includes Mec1 in yeast, senses damaged or aberrant DNA and then triggers cell cycle arrest and repair. Cha and Kleckner (p. 602) show that in the absence of Mec1, DNA breaks occur in specific regions of chromatin, christened replication slow zones. Thus, Mec1 plays a role in replication fork progression during normal S-phase of the cell cycle.

  7. Moving Up the Ladder Together

    Complex interactions occur in the two-dimensional planes of layered copper oxide superconductors. One route to unraveling this complexity is to look for common behavior in simpler oxide materials. Blumberg et al. (p. 584) adopt this route to probe the spectroscopic, transport, and dielectric properties of the Sr14Cu24O41 ladder compounds, materials that contain two-legged fragments of the CuO plane. The insulating phase forms a charge-ordered state that is depinned at low electric field and that may represent a new ground state of the cuprate superconductors.

  8. Pain in the Gut

    Helicobacter pylori, which infects around 50% of people around the world, can cause peptic ulcers and has been linked to gastric cancer. Mahdavi et al. (p. 573) have now isolated a receptor termed the sialic acid binding adhesin on H. pylori that binds to inflammation-induced sialyl-Lewis × (sLex) antigens on the gastric mucosa. Biopsies from infected and uninfected individuals show that the level of sLex is increased in infection. The interaction between the sLex and the adhesin may thus contribute to the virulence and to the chronicity of H. pylori infections.

  9. Damage-Response Team

    A group of rare inherited disorders that are characterized by cellular sensitivity to DNA-damaging agents and chromosome instability have helped researchers piece together the molecular pathways by which cells respond to DNA damage. Howlett et al. (p. 606; see Perspective by Witt and Ashworth) have now found that a small subset of patients with the chromosome instability syndrome Fanconi anemia (FA) have biallelic mutations in the breast cancer susceptibility gene BRCA2. The BRCA2 protein, which is believed to function as part of the homologous recombination machinery, may function in the same DNA-repair pathway as the six previously characterized FA proteins. Further dissection of this pathway may reveal new targets for therapeutic intervention.

  10. Revisiting a Controversial Diet Drug

    Fenfluramine (d-FEN) was once widely prescribed in the United States as a weight loss medication, but it was withdrawn from the market in 1997 after reports of valvular heart disease and hypertension in a subset of patients taking the drug. As an appetite suppressant, d-FEN increases the availability of the neurotransmitter serotonin, but the central pathways that mediate the drug's anorectic effects have not been identified. Studying rodent models, Heisler et al. (p. 609) now report that d-FEN activates melanocortin signaling pathways in the arcuate nucleus of the hypothalamus, a system already well known to play a pivotal role in maintenance of energy balance in both rodents and humans. This new mechanistic information could aid in the development of less risky drugs for weight loss.

  11. Getting It Straight

    The assembly of actin filaments is required for processes such as cell division, the establishment and maintenance of cell polarity, and cell motility. The formation of branched actin filaments is now well understood, but how cells produce unbranched actin cables has been somewhat mysterious. Pruyne et al. (p. 612; see the Perspective by Chang and Peter) show how the formin homology domain on a yeast protein promotes the formation of unbranched actin filaments in vitro.

    CREDIT: PRUYNE ET AL.
  12. Sorting Out Receptors

    What are the mechanisms by which different G protein-coupled receptors (GPCRs) are recycled to the cell surface or targeted to the lysosomes for degradation? Whistler et al. (p. 615; see the Perspective by Gray and Roth) describe the role that one protein, GASP (GPCR-associated sorting protein), plays in the fate of two structurally related opioid GPCRs. The carboxyl-terminal cytoplasmic domain of the delta opioid receptor, but not that of the mu opioid receptor, binds to GASP, and this interaction promotes transport to the lysosome. Several other endocytic receptors also interact with GASP, which appears to be a key player in regulating sorting to lysosomes versus recycling after endocytosis.

  13. Homing in on Autoimmune Genes

    Only few specific gene loci have been defined for autoimmune diseases. In mice, Bphs is an autosomal dominant locus influencing susceptibility to organ-specific autoimmunity. The susceptible phenotype controlled by Bphs also displays increased hypersensitivity to vasoactive amines (VAAS) induced by pertussis toxin. Ma et al. (p. 620) now show that the histamine H1 receptor (H1R) gene, Hrh1, encodes Bphs and that a three-amino acid difference could account for activity of the susceptibility locus. Deletion of Hrh1 conferred resistance in a susceptible strain of mice to induced VAAS, as well as two forms of experimentally induced autoimmunity. Resistance correlated with reversal of T helper phenotype, which suggests that the Bphs locus confers susceptibility via dysregulation of T cell responses.

  14. Probing Bulk Charge Inhomogeneites in Cuprates

    Recent experiments on the high-temperature cuprate superconductors suggest that they are inhomogeneous; modulations of their charge density have been observed over nanometer-length scales. However, as the experiments have been based on surface measurements, there exists the possibility that the effects may be an artifact of the techniques. Abbamonte et al. (p. 581; see the news story by Cho) introduce a technique based on the resonant x-ray scattering, where the x-ray wavelength is tuned to the oxygen K edge and allows the charge densities to be probed. In the La2CuO4+δ, they found no evidence for in-plane hole ordering.

  15. Made to Measure

    Combinatorial libraries of molecules can be useful in the search for molecules that strongly bind a receptor, such as a drug target. However, the pool of molecules in such libraries is fixed, limiting the range of molecules that can be found. In contrast, the library members in a dynamic combinatorial library can assemble reversibly into a variety of larger species. In the presence of the receptor, the formation of certain species should be favored. Otto et al. (p. 590) use such a library to show that molecular recognition of a template can lead to sizable shifts in the library composition, allowing the identification of those species that bind the template most strongly. These species can then be synthesized selectively by using a library that contains only those building blocks selected by the template.

  16. The Worm's Turn

    The nematode Caenorhabditis elegans has been used by Kim et al. (p. 623) to screen for genes involved in the control of infection by the Gram-negative bacterium Pseudomonas aeruginosa. Two mutant worms were identified that had normal fitness and life cycles but that were rapidly killed by P. aeruginosa as the bacteria accumulated in the intestine. The worm mutants are also sensitive to the Gram-positive pathogen Enterococcus faecalis. Genetic mapping, sequencing of mutant alleles, and rescue with genomic DNA fragments show that the genes involved encode homologs of elements of the mammalian p38 mitogen-activated protein kinase pathway known to be important in cellular immune responses.

  17. Antiangiogenic Therapy and p53

    Yu et al. (Reports, 22 Feb. 2002, p. 1526) offered evidence that tumors in which the p53 tumor suppressor gene has been inactivated (which happens in about half of human cancers) are less responsive to antiangiogenic therapy than tumors with normal p53 function, a finding that raised a potential obstacle to cancer therapies involving angiogenesis inhibitors. Giaccia and Hammond, in a comment, question whether the HCT116 cell lines used in the Yu et al. study were appropriately chosen and hold that “more data are needed before [the study's] relevance to antiangiogenic therapy can be considered.” Browder et al., in a separate comment, maintain that the study's results “have been widely misinterpreted to imply that antiangiogenesis therapy will eventually fail,” even though growth of both p53+/+ and p53−/− cells in the study were “clearly inhibited” by antiangiogenic therapy. Kerbel et al., in their response, discuss both the specific technical issues raised by Hammond and Giaccia and the broad implications of the Yu et al. study for antiangiogenic therapy.

    The full text of these comments can be seen at www.sciencemag.org/cgi/content/full/297/5581/471a

  18. BIOMEDICINE

    D-Day for BRCA2

    1. Emily Witt,
    2. Alan Ashworth*
    1. The authors are at The Breakthrough Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK. E-mail: elisa{at}icr.ac.uk

    Important discoveries are sometimes so neat and satisfying that, in retrospect, they seem obvious. So it is with the finding described by Howlett et al. (1) on page 606 of this issue. These authors disclose that the inheritance of two defective copies of the BRCA2 breast cancer susceptibility gene (2) can lead to Fanconi anemia (FA) (3), a complex disorder characterized by congenital abnormalities, progressive bone marrow failure, and cancer susceptibility.

    Heterozygous carriers of BRCA2 mutations inherit a high risk of developing breast cancer (up to 85%) and other cancers such as ovarian and pancreatic. No developmental or other obvious defects have been noted in these individuals. The BRCA2 protein is thought to be important in the repair of DNA damage by homologous recombination, at least in part by regulating the activity of RAD51 (2). Cells lacking BRCA2 inaccurately repair damaged DNA, leading to gene mutation and progression of tumors, and are particularly sensitive to DNA cross-linking agents.

    Most patients with FA present within the first decade of life with bone marrow failure and cancer, typically acute myeloid leukemia and squamous cell carcinoma, usually of the head and neck (3). This is accompanied by congenital abnormalities such as growth retardation and skeletal defects (microcephaly and absent radii or thumbs), kidney defects, and abnormal skin pigmentation. The heterogeneity of the disease leads to difficulties in making a firm clinical diagnosis, and therefore the cellular hypersensitivity to DNA cross-linking agents such as mitomycin C that these patients exhibit is used as the gold standard diagnostic tool.

    FA is a recessively inherited disorder that can result from mutation in at least eight individual genes (3). Apart from genes B and D1, these have all been isolated previously and encode diverse proteins, many of which interact within a cellular complex related to the maintenance of genomic stability.

    Howlett et al. (1) show that one of the previously unidentified FA genes, FANCD1, is in fact BRCA2. The cellular consequences of homozygosity for BRCA2 mutation—spontaneous chromosome instability and hypersensitivity to DNA cross-linking agents—are similar to those in cells derived from FA patients. This prompted the authors to determine the sequence of the BRCA2 gene in FANCD1 patients. One individual with FA carried two different truncating mutations in BRCA2 typical of those that cause susceptibility to breast cancer when heterozygous. Individuals carrying two BRCA2 mutations have not been reported before, and this result was surprising as it was thought likely that this combination of mutations would be lethal. An explanation for this finding might be suggested, however, by previous work on BRCA2 knockout mice. Mice homozygous for mutations that eliminate most of the BRCA2 gene do die early in embryogenesis, whereas those with apparently milder (“hypomorphic”) mutations can survive to adulthood (4, 5). It is intriguing that these mice have some phenotypes that are reminiscent of FA, including small gonads, skeletal defects, and sensitivity to DNA cross-linking agents (4, 5). It is possible therefore that only hypomorphic BRCA2 mutations lead to FA, whereas stronger mutations are lethal during embryogenesis. The final piece of evidence implicating BRCA2 in the pathogenesis of FA is the partial rescue of sensitivity to mitomycin C of a FANCD1 cell line by introduction of a wild-type BRCA2 gene (1). Although this result, in itself, is open to alternative interpretation, taken together with the genetic data, it provides a persuasive argument for the role of BRCA2 mutation in FA. Preliminary evidence is also presented by the authors for a role of BRCA2 mutation in another FA complementation group, FANCB, although this requires additional confirmation.

    This is not the first link between FA and breast cancer susceptibility. Another FA complementation group protein, FANCD2, can interact and colocalize with BRCA1 (6). Moreover, both FANCD2 protein and BRCA1 can be phosphorylated by ATM, itself recently implicated in susceptibility to breast cancer (7, 8). Thus, it seems that the pathways disrupted in FA and breast cancer susceptibility are intimately connected on several levels (see the figure).

    DNA repair proteins implicated in Fanconi anemia and breast cancer susceptibility.

    The Fanconi anemia proteins are thought to be present in the nucleus as a complex. ATM can phosphorylate FANCD2, BRCA1, and CHEK2. FANCD2 can interact with BRCA1 and may be a substrate for its ubiquitin ligase activity. FANCD1/BRCA2 is thought to lie downstream of FANCD2 and can associate with BRCA1. BRCA2 binds RAD51, which is involved in repair of damaged DNA. Heterozygosity for BRCA1, BRCA2, ATM, and CHEK2 has been implicated in breast cancer susceptibility (2, 8, 10). Homozygosity for FANC and BRCA2 genes causes Fanconi anemia (1, 3).

    So if BRCA2 can be an FA gene, could other FA genes be new BRCA genes? Little evidence could be found in previous studies for an excess of cancers in relatives of FA patients (9). Nevertheless, this work could not take into account the existence of multiple genes for FA; if only some behaved like BRCA2, the analysis would be negative. It would be particularly interesting to examine FANCD2, with what appears to be a central role in the pathway (see the figure). Doubtless the new work by Howlett et al. (1) will stimulate considerable interest in readdressing the issue of cancer susceptibility in FA heterozygotes.

    Only a small proportion of the cases of FA, which in itself is rare, is caused by BRCA2 mutation. But the importance of this finding is that it connects two previously different bodies of work on DNA repair. Doubtless this will fuel progress into understanding both breast cancer and FA.

    References

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