Hot off the presses! Dec 11 Cell

The Dec 11 issue of the Cell is now up on Pubget (About Cell): if you're at a subscribing institution, just click the link in the latest link at the home page. (Note you'll only be able to get all the PDFs in the issue if your institution subscribes to Pubget.)

Latest Articles Include:

• Switching on Epigenetic Therapy
  - Cell 139(6):1029-1031 (2009)
  Reversible epigenetic changes that alter gene expression are a characteristic of many cancers and other diseases. Biotech companies are taking note and are starting to develop new drugs to reverse such pathogenic "epimutations."
• The Ends Have Arrived
  - Cell 139(6):1038-1040 (2009)
  The 2009 Nobel Prize in Physiology or Medicine has been awarded to Elizabeth Blackburn, Carol Greider, and Jack Szostak for their contributions to our understanding of how the ends of eukaryotic chromosomes, telomeres, are replicated by a specialized reverse transcriptase, telomerase. I present a personal view of the telomere field, putting the contributions of these three Nobel laureates into historical context.
• Bone Appétit!
  - Cell 139(6):1044-1045 (2009)
  
• During Transitions Proteins Make Fleeting Bonds
  - Cell 139(6):1049-1051 (2009)
  How do proteins efficiently and precisely shift from one conformation to another? Gardino et al. (2009) show that transient hydrogen bonds are critical to the conformational transition of the nitrogen regulatory protein NtrC between its native state and its active state.
• A Tethering Complex Recruits SNAREs and Grabs Vesicles
  - Cell 139(6):1053-1055 (2009)
  Protein tethers can bridge gaps between membranes. Ren et al. (2009) now provide evidence that the yeast Dsl1 complex tethers vesicles to the endoplasmic reticulum (ER) by binding ER SNARE proteins at its base and capturing vesicles using a loop region that extends 20 nm from the ER membrane.
• Nuclear Receptor-Induced Chromosomal Proximity and DNA Breaks Underlie Specific Translocations in Cancer
  Lin C Yang L Tanasa B Hutt K Ju BG Ohgi K Zhang J Rose DW Fu XD Glass CK Rosenfeld MG - Cell 139(6):1069-1083 (2009)
  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.
• Conserved MicroRNA miR-8/miR-200 and Its Target USH/FOG2 Control Growth by Regulating PI3K
  - Cell 139(6):1096-1108 (2009)
  How body size is determined is a long-standing question in biology, yet its regulatory mechanisms remain largely unknown. Here, we find that a conserved microRNA miR-8 and its target, USH, regulate body size in Drosophila. miR-8 null flies are smaller in size and defective in insulin signaling in fat body that is the fly counterpart of liver and adipose tissue. Fat body-specific expression and clonal analyses reveal that miR-8 activates PI3K, thereby promoting fat cell growth cell-autonomously and enhancing organismal growth non-cell-autonomously. Comparative analyses identify USH and its human homolog, FOG2, as the targets of fly miR-8 and human miR-200, respectively. USH/FOG2 inhibits PI3K activity, suppressing cell growth in both flies and humans. FOG2 directly binds to p85α, the regulatory subunit of PI3K, and interferes with the formation of a PI3K complex. Our study identifies two novel regulators of insulin signaling, miR-8/miR-200 and USH/FOG2, and suggests th! eir roles in adolescent growth, aging, and cancer.
• A Structure-Based Mechanism for Vesicle Capture by the Multisubunit Tethering Complex Dsl1
  - Cell 139(6):1119-1129 (2009)
  Vesicle trafficking requires membrane fusion, mediated by SNARE proteins, and upstream events that probably include "tethering," an initial long-range attachment between a vesicle and its target organelle. Among the factors proposed to mediate tethering are a set of multisubunit tethering complexes (MTCs). The Dsl1 complex, with only three subunits, is the simplest known MTC and is essential for the retrograde traffic of COPI-coated vesicles from the Golgi to the ER. To elucidate structural principles underlying MTC function, we have determined the structure of the Dsl1 complex, revealing a tower containing at its base the binding sites for two ER SNAREs and at its tip a flexible lasso for capturing vesicles. The Dsl1 complex binds to individual SNAREs via their N-terminal regulatory domains and also to assembled SNARE complexes; moreover, it is capable of accelerating SNARE complex assembly. Our results suggest that even the simplest MTC may be capable of orchestr! ating vesicle capture, uncoating, and fusion.
• Platelet Polyphosphates Are Proinflammatory and Procoagulant Mediators In Vivo
  - Cell 139(6):1143-1156 (2009)
  Platelets play a central role in thrombosis, hemostasis, and inflammation. We show that activated platelets release inorganic polyphosphate (polyP), a polymer of 60–100 phosphate residues that directly bound to and activated the plasma protease factor XII. PolyP-driven factor XII activation triggered release of the inflammatory mediator bradykinin by plasma kallikrein-mediated kininogen processing. PolyP increased vascular permeability and induced fluid extravasation in skin microvessels of mice. Mice deficient in factor XII or bradykinin receptors were resistant to polyP-induced leakage. PolyP initiated clotting of plasma via the contact pathway. Ablation of intrinsic coagulation pathway proteases factor XII and factor XI protected mice from polyP-triggered lethal pulmonary embolism. Targeting polyP with phosphatases interfered with procoagulant activity of activated platelets and blocked platelet-induced thrombosis in mice. Addition of polyP restored defective plas! ma clotting of Hermansky-Pudlak Syndrome patients, who lack platelet polyP. The data identify polyP as a new class of mediator having fundamental roles in platelet-driven proinflammatory and procoagulant disorders.
• Prediction of Photoperiodic Regulators from Quantitative Gene Circuit Models
  - Cell 139(6):1170-1179 (2009)
  Photoperiod sensors allow physiological adaptation to the changing seasons. The prevalent hypothesis is that day length perception is mediated through coupling of an endogenous rhythm with an external light signal. Sufficient molecular data are available to test this quantitatively in plants, though not yet in mammals. In Arabidopsis, the clock-regulated genes CONSTANS (CO) and FLAVIN, KELCH, F-BOX (FKF1) and their light-sensitive proteins are thought to form an external coincidence sensor. Here, we model the integration of light and timing information by CO, its target gene FLOWERING LOCUS T (FT), and the circadian clock. Among other predictions, our models show that FKF1 activates FT. We demonstrate experimentally that this effect is independent of the known activation of CO by FKF1, thus we locate a major, novel controller of photoperiodism. External coincidence is part of a complex photoperiod sensor: modeling makes this complexity explicit and may thus contribute ! to crop improvement.
• Evolution of the tan Locus Contributed to Pigment Loss in Drosophila santomea: A Response to Matute et al.
  - Cell 139(6):1189-1196 (2009)
  We have shown previously that the loss of abdominal pigmentation in D. santomea relative to its sister species D. yakuba resulted, in part, from cis-regulatory mutations at the tan locus. Matute et al. claim, based solely upon extrapolation from genetic crosses of D. santomea and D. melanogaster, a much more divergent species, that at least four X chromosome regions but not tan are responsible for pigmentation differences. Here, we provide additional evidence from introgressions of D. yakuba genes into D. santomea that support a causative role for tan in the loss of pigmentation and present analyses that contradict Matute et al.'s claims. We discuss how the choice of parental species and other factors affect the ability to identify loci responsible for species divergence, and we affirm that all of our previously reported results and conclusions stand.