A backup DNA repair pathway moves to the forefront

Chromosomal translocations between antigen receptor loci and oncogenes are a hallmark of lymphoid cancers. Several new studies now reveal that programmed DNA breaks created during assembly of antigen receptor genes can be channeled into an alternative DNA end-joining pathway that is implicated in the chromosomal translocations of lymphoid cancers (Corneo et al., 2007; Soulas-Sprauel et al., 2007; Yan et al., 2007).     

Characterization of the molten globule of human serum retinol-binding protein using NMR spectroscopy

The molten globule state is a partially folded conformer of proteins that has been the focus of intense study for more than two decades. This non-native fluctuating conformation has been linked to protein-folding intermediates, to biological function, and more recently to precursors in amyloid fibril formation. The molten globule state of human serum retinol-binding protein (RBP) has been postulated previously to be involved in the mechanism of ligand release (Ptitsyn, O. B., et al. (1993) FEBS Lett. 317, 181-184). Conserved residues within RBP have been identified and proposed to be key to folding and stability, although a link to a molten globule state has not previously been shown (Greene, L. H., et al. (2003) FEBS Lett. 553, 39-44). In this work, a detailed characterization of the acid-induced molten globule of RBP is presented. Using stopped-flow fluorescence spectroscopy in the presence of 8-anilino-1-naphthalene sulfonic acid (ANS), we show that RBP populates a state with molten-globule-like characteristics early in refolding. To gain insight into the structural features of the molten globule of RBP, we have monitored the denaturant-induced unfolding of this ensemble using NMR spectroscopy. The transition at the level of individual residues is significantly more cooperative than that found previously for the archetypal molten globule, alpha-lactalbumin (alpha-LA); this difference may be due to a predominantly beta-sheet structure present in RBP in contrast to the alpha-helical nature of the alpha-LA molten globule.     

H3K27 demethylases, at long last

Methylation of lysine 27 on histone H3 (H3K27me) by the Polycomb complex (PRC2) proteins is associated with gene silencing in many developmental processes. A cluster of recent papers (Agger et al., 2007; De Santa et al., 2007; Lan et al., 2007; Lee et al., 2007) identify the JmjC-domain proteins UTX and JMJD3 as H3K27-specific demethylases that remove this methyl mark, enabling the activation of genes involved in animal body patterning and the inflammatory response.     

Bone remodeling, energy metabolism, and the molecular clock

The adult skeleton is constantly renewed through bone remodeling. Four recent papers (Baldock et al., 2007; Lee et al., 2007; Lundberg et al., 2007; Sato et al., 2007) provide new insights into central and peripheral control of this remodeling sequence. Two of the studies add to our knowledge of the complex hypothalamic modulation of bone turnover mediated by NMU and NPY via the sympathetic nervous system, while the other two focus on the peripheral neural target, the osteoblast, and its regulation by neuropeptides and osteocalcin. These findings support a new paradigm concerning the regulation of bone remodeling and provide a foundation for novel approaches to preventing osteoporosis.     

Attraction and the single cell

Selective expression of the eotaxin receptor CCR3 by human T helper 2 cellsSallusto, F. et al. (1997)Science 277, 2005–2007Functional expression of the eotaxin receptor CCR3 in T lymphocytes co-localising with eosinophilsGerber, B.O. et al. (1997)Curr. Biol. 7, 836–843Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2sBonecchi, R. et al. (1998)J. Exp. Med. 187, 129–134CCR5 is characteristic of Th1 lymphocytesLoetscher, M. et al. (1998)Nature 391, 344–345     

PTEN enters the nuclear age

Regulation of the PTEN tumor suppressor protein is poorly understood. In this issue, Wang et al. (2007) and Trotman et al. (2007) describe how ubiquitination regulates PTEN stability and its nuclear localization. Additionally, Shen et al. (2007) report that a nuclear pool of PTEN helps to maintain chromosomal stability.     

视黄醇结合蛋白RBP4可与多种核受体相互作用

视黄醇结合蛋白 (retinolbindingprotein ,RBP4 )是体内一种重要的转运蛋白 ,主要负责结合、转运全反式视黄醇 (维生素A ,VitA ) .VitA及其衍生物如11 cis 视黄醛、all trans 视黄酸等 ,均是体内非常重要的疏水分子 ,与视觉循环、胚胎发育等多种过程有关 .RBP4的功能障碍会导致     

On again, off again: the SRC-3 transcriptional coactivator moonlights as a translational corepressor

In a recent issue of Molecular Cell, Yu et al. (2007) reported that the steroid receptor coactivator-3 (SRC-3) has a novel cytoplasmic function: it activates the translational silencers TIA-1 and TIAR and thus inhibits the translation of proinflammatory cytokines.     

RBP45 and RBP47, two oligouridylate-specific hnRNP-like proteins interacting with poly(A)+ RNA in nuclei of plant cells

Introns in plant nuclear pre-mRNAs are highly enriched in U or U + A residues and this property is essential for efficient splicing. Moreover, 3'-untranslated regions (3'-UTRs) in plant pre-mRNAs are generally UA-rich and contain sequences that are important for the polyadenylation reaction. Here, we characterize two structurally related RNA-binding proteins (RBPs) from Nicotiana plumbaginifolia, referred to as RBP45 and RBP47, having specificity for oligouridylates. Both proteins contain three RBD-type RNA-binding domains and a glutamine-rich N-terminus, and share similarity with Nam8p, a protein associated with U1 snRNP in the yeast Saccharomyces cerevisiae. Deletion analysis of RBP45 and RBP47 indicated that the presence of at least two RBD are required for interaction with RNA and that domains other than RBD do not significantly contribute to binding. mRNAs for RBP45 and RBP47 and mRNAs encoding six related proteins in Arabidopsis thaliana are constitutively expressed in different plant organs. Indirect immunofluorescence and fractionation of cell extracts showed that RBP45 and RBP47 are localized in the nucleus. In vivo UV crosslinking experiments demonstrated their association with the nuclear poly(A)+ RNA. In contrast to UBP1, another oligouridylate-binding nuclear three-RBD protein of N. plumbaginifolia (Lambermon et al., EMBO J, 2000, 19:1638-1649), RBP45 and RBP47 do not stimulate mRNA splicing and accumulation when transiently overexpressed in protoplasts. Properties of RBP45 and RBP47 suggest they represent hnRNP-proteins participating in still undefined steps of pre-mRNA maturation in plant cell nuclei.     

Aging: all in the head?

Global reduction in insulin signaling has been linked to extended life span in a range of organisms. New work on mice with brain-specific or whole-body reductions in insulin receptor substrate 2 (IRS2) (Taguchi et al., 2007) points to a role for insulin/IGF-1 signaling in the central control of mammalian aging.     

After hours keeps clock researchers CRYing Overtime

Three recent reports, including one in this issue of Cell, reveal that the circadian regulator CRY is targeted for degradation by the F box E3 ubiquitin ligase FBXL3 (Siepka et al., 2007; Busino et al., 2007; Godinho et al., 2007). These studies confirm the importance of targeted protein degradation as a key design feature of the mammalian circadian clock.     

Mighty Piwis defend the germline against genome intruders

Piwis are a germline-specific subclass of the Argonaute family of RNA interference (RNAi) effector proteins that are associated with a recently discovered group of small RNAs (piRNAs). Recent studies in Drosophila and zebrafish directly implicate Piwi proteins in piRNA biogenesis to maintain transposon silencing in the germline genome (Brennecke et al., 2007; Gunawardane et al., 2007; Houwing et al., 2007). This function may be conserved in mice as loss of Miwi2, a mouse Piwi homolog, leads to germline stem cell and meiotic defects correlated with increased transposon activity (Carmell et al., 2007).     

Epigenetic Variations in Plant Hybrids and Their Potential Roles in Heterosis

Heterosis,one of the most important biological phenomena,refers to the phenotypic superiority of a hybrid over its genetically diverse parents with respect to many traits such as biomass,growth rate and yield.Despite its successful application in breeding and agronomic production of many crop and animal varieties,the molecular basis of heterosis remains elusive.The classic genetic explanations for heterosis centered on three hypotheses:dominance (Davenport,1908;Bruce,1910;Keeble and Pellew,1910;Jones,1917),overdominance (East,1908;Shull,1908) and epistasis (Powers,1944;Yu et al.,1997).However,these hypotheses are largely conceptual and not connected to molecular principles,and are therefore insufficient to explain the molecular basis of heterosis (Birchler et al.,2003).Recently,many studies have explored the molecular mechanism of heterosis in plants at a genome-wide level.These studies suggest that global differential gene expression between hybrids and parental lines potentially contributes to heterosis in plants (e.g.,Swanson-Wagner et al.,2006;Zhang et al.,2008;Wei et al.,2009;Song et al.,2010).Research suggests that genetic components,including cis-acting elements and trans-acting factors,are critical regulators of differential gene expression in hybrids (Hochholdinger and Hoecker,2007;Springer and Stupar,2007;Zhang et al.,2008).However,other research indicates that epigenetic components,the regulators of chromatin states and genome activity,also have the potential to impact heterosis (e.g.,Ha et al.,2009;He et al.,2010;Groszmann et al.,2011;Barber et al.,2012;Chodavarapu et al.,2012;Greaves et al.,2012a;Shen et al.,2012).     

New insights into manganese toxicity and speciation

Manganese (Mn) is known to be a neurotoxic agent for nearly 175 years now. A lot of research has therefore been carried out over the last century. From preliminary describing only symptoms of Mn-(over)exposed workers, research was preceded to more detail on toxic mechanisms of Mn. Unraveling those neurotoxic mechanisms implicated a number of studies, which were summarized partly in several reviews (e.g. Yokel RA. Neuromol Med 2009;11(4):297–310; Aschner M, et al. Toxicology Appl Pharmacol 2007;221(2):131–47; Michalke B, et al. J Environ Monit 2007;9(7):650). Since our recent review on Mn-speciation in 2007 (Michalke B, et al. J Environ Monit 2007;9(7):650), Mn-research was considerably pushed forward and several new research articles were published. The very recent years though, Mn toxicity investigating science is spreading into different fields with very detailed and complex study designs. Especially the mechanisms of Mn-induced neuronal injury on cellular and molecular level was investigated in more detail, discussing neurotransmitter and enzyme interactions, mechanisms of action on DNA level and even inclusion of genetic influences. Depicting the particular Mn-species was also a big issue to determine which molecule is transporting Mn at the cell membranes and which one is responsible for the injury of neuronal tissue. Other special foci on epidemiologic studies were becoming more and more important: These foci were directed toward environmental influences of Mn on especially Parkinson disease prevalence and the ability to carry out follow-up studies about Mn-life-span exposure. All these very far-reaching research applications may finally lead to a suitable future human Mn-biomonitoring for being able to prevent or at least detect the early onset of manganism at the right time.     

DisSIRTing on LXR and cholesterol metabolism

The NAD-dependent deacetylase SIRT1 regulates lipid and carbohydrate metabolism and has been shown to extend life span in several species. In a recent issue of Molecular Cell, Li et al. (2007) demonstrate that SIRT1 deacetylates and activates the nuclear receptor LXR by favoring its ligand-dependent proteasomal degradation, thereby potentially regulating reverse cholesterol transport.     

Thrombopoietin, HSCs, and the osteoblast niche: holding on loosely, but not letting G0

New findings in this issue of Cell Stem Cell by Qian et al. (2007) and Yoshihara et al. (2007) reveal that thrombopoietin modulates hematopoietic stem cell (HSC) cell-cycle progression at the osteoblast surface, linking a single cytokine with a specific postnatal niche cell. These observations indicate that simultaneous stimulation and suspension in a G(0) state are critical for maintenance of the HSC pool.