What was the evolutionary synthesis?

There has not been another scientific revolution that caused as much turmoil and dissension as the darwinian one. For almost 80 years it was again and again pronounced to be a failure and to be totally refuted, and at least three major alternatives were proposed to replace it. Yet, in the 1930s-1940s the opposing views were quickly and decisively refuted and a largely unified evolutionary theory emerged. Why and how this happened, however, is still rather controversial.     

Origins of tmRNA: the missing link in the birth of protein synthesis?

The RNA world hypothesis refers to the early period on earth in which RNA was central in assuring both genetic continuity and catalysis. The end of this era coincided with the development of the genetic code and protein synthesis, symbolized by the apparition of the first non-random messenger RNA (mRNA). Modern transfer-messenger RNA (tmRNA) is a unique hybrid molecule which has the properties of both mRNA and transfer RNA (tRNA). It acts as a key molecule during trans-translation, a major quality control pathway of modern bacterial protein synthesis. tmRNA shares many common characteristics with ancestral RNA. Here, we present a model in which proto-tmRNAs were the first molecules on earth to support non-random protein synthesis, explaining the emergence of early genetic code. In this way, proto-tmRNA could be the missing link between the first mRNA and tRNA molecules and modern ribosome-mediated protein synthesis.     

The ordered secretion of bioactive peptides: oldest or newest first?

The order of secretion of newly synthesized and older bioactive peptides was investigated using primary rat intermediate pituitary melanotropes, which synthesize, store, and secrete peptides derived from pro-ACTH/endorphin (PAE; also POMC). PAE-derived peptides produced by the cells were biosynthetically labeled by incubating the cells with radioactive amino acids at various times preceding the period during which secretion was examined; secreted and cellular peptides were characterized and quantitated by immunoprecipitation, using affinity-purified antibodies to selected regions of PAE, followed by polyacrylamide gel electrophoretic analysis. Release in the absence of secretagogues (basal or constitutive release) was compared to release in the presence of maximally effective levels of 8-bromo-cAMP and BaCl2 (stimulated or regulated release). Both cell types showed short-lived preferential basal release of newly synthesized and not fully mature peptides (less than 2-3 h old). Conversely, the cells showed preferential stimulated secretion of older peptides. A process of maturation occurred, taking 2-4 h, after which the secretion of newly synthesized and older peptides in response to secretagogues was nearly indistinguishable for the smallest product peptides. The data support a model of gradual processing of peptides from precursors into smaller products and maturation from molecules only available for basal release into peptides available for stimulated secretion as well as for basal release. Basal secretion was found to include mature peptides as well as intermediates and precursor molecules. The data do not support the existence of any preferential regulated secretion of newly synthesized peptides.     

Ageing and the regulation of protein synthesis: a balancing act?

Ageing in diverse species ranging from yeast to humans is associated with extensive changes in both general and specific protein synthesis. Accumulating evidence now indicates that these alterations are not simply a corollary of the ageing process but, rather, they have a causative role in senescent decline. Indeed, interfering with mRNA translation significantly influences longevity. Interestingly, the mechanisms that control mRNA translation interface with intricate, conserved signalling pathways and specific conditions that regulate ageing, such as the insulin-insulin growth factor 1 signalling pathway and caloric restriction. This emerging relationship reveals that protein synthesis is a novel determinant of ageing in diverse organisms such as yeast, worms, flies and mice and can thus be considered as a universal component of the ageing process.     

Platelet function and Isoprostane biology. Should Isoprostanes be the newest member of the Orphan-ligand family?

While there have been many reports investigating the biological activity and signaling mechanisms of isoprostanes, their role in biology, particularly in platelets, appears to still be underestimated. Moreover, whether these lipids have their own receptors is still debated, despite multiple reports that discrete receptors for isporpstanes do exist on platelets, vascular tissues, amongst others. This paper provides a review of the important literature of isoprostanes and provides reasoning that isoprostanes should be classified as orphan ligands until their receptor(s) is/are identified.     

Does protein synthesis occur in the nucleus?

Although it is universally accepted that protein synthesis occurs in the cytoplasm, the possibility that translation can also take place in the nucleus has been hotly debated. Reports have been published claiming to demonstrate nuclear translation, but alternative explanations for these results have not been excluded, and other experiments argue against it. Much of the appeal of nuclear translation is that functional proofreading of newly made mRNAs in the nucleus would provide an efficient way to monitor mRNAs for the presence of premature termination codons, thereby avoiding the synthesis of deleterious proteins. mRNAs that are still in the nucleus-associated fraction of cells are subject to translational proofreading resulting in nonsense-mediated mRNA decay and perhaps nonsense-associated alternate splicing. However, these mRNAs are likely to be in the perinuclear cytoplasm rather than within the nucleus. Therefore, in the absence of additional evidence, we conclude that nuclear translation is unlikely to occur.     

Cyclin synthesis: Who needs it?

Studies of the G2 to M transition in amphibian oocytes, in combination with in vitro mitotic systems and yeast genetic analysis, have significantly contributed to our understanding of the mechanisms by which M-phase is regulated. Historically, oocyte maturation has provided a number of valuable initial observations, but the biochemical elucidation of cell cycle control mechanisms has proved more tractable in cell-free extracts of frog eggs which reproduce aspects of early embryogenic mitosis. Recent experiments examining the importance of protein synthesis in the maturing oocyte have highlighted some important differences between mitosis and meiosis. Additional controls found in meiosis but not embryonic mitosis, are similar to controls found in somatic cells. This suggests that understanding the differences, as well as the similarities, between meiosis in the oocyte and mitosis in the early embryo will help us to learn more about the way in which cells enter and leave mitosis.     

NO signal at the crossroads: polyamine-induced nitric oxide synthesis in plants?

Polyamines, such as spermine, spermidine and putrescine, are ubiquitous polycationic compounds that are produced by almost all living organisms, including plants, animals, fungi and bacteria. Polyamines are multifunctional and interact with polyanionic biomolecules such as DNA or protein. However, despite their potential significance, the polyamine-dependent signal transduction system has not been revealed yet. Ni Ni Tun and colleagues have recently reported a possible linkage between polyamine and nitric oxide (NO), another ubiquitous signalling molecule.     

The exocyst meets the translocon: a regulatory circuit for secretion and protein synthesis?

The translocon is responsible for the translocation of proteins across the membrane of the endoplasmic reticulum into its lumen, whereas the exocyst acts at the other end of the secretory pathway, tethering secretory vesicles to the sites of exocytosis. Here, we discuss three independent lines of evidence that indicate surprising genetic, physical and functional interactions between the two complexes. Although much of the existing evidence is rather preliminary in nature, these interactions might serve to coordinate the biosynthetic capacity of the cell with the function of the secretory machinery.     

Does malonate take part in the synthesis of sterols?

The effect of acetyl-CoA-carboxylase activators, citrate and biotin, on cholesterol biosynthesis from acetate and malonate in rat liver and in cultured human lung fibroblasts was studied. Administration of citrate and biotin to animals and an addition of biotin to the fibroblast culture medium led to a significant stimulation of [2-14C]acetate incorporation into sterols but had no effect on the incorporation of [2-14C]malonate. The data obtained suggest that malonate is incorporated into sterols without preliminary decarboxylation.     

Does trans-lesion synthesis explain the UV-radiation resistance of DNA synthesis in C. elegans embryos?

Over 10-fold larger fluences were required to inhibit both DNA synthesis and cell division in wild-type C. elegans embryos as compared with other model systems or C. elegans rad mutants. In addition, unlike in other organisms, the molecular weight of daughter DNA strands was reduced only after large, superlethal fluences. The molecular weight of nascent DNA fragments exceeded the interdimer distance by up to 19-fold, indicating that C. elegans embryos can replicate through non-instructional lesions. This putative trans-lesion synthetic capability may explain the refractory nature of UV radiation on embryonic DNA synthesis and nuclear division in C. elegans.     

Assembly of vaccinia virus revisited: de novo membrane synthesis or acquisition from the host?

In 1968 it was proposed that the first membrane structures that assemble in vaccinia virus-infected cells, the crescents, are formed by a unique viral mechanism in which a single membrane bilayer is synthesized de novo. 25 years later it was suggested that the vaccinia membranes are derived from an organelle that is part of the host cell's secretory pathway, the intermediate compartment (IC), and that the viral crescents are made of two tightly apposed membranes rather than a single bilayer. Several independent studies have subsequently shown that membrane proteins of the intracellular mature virus (IMV) insert co-translationally into endoplasmic reticulum (ER) membranes, and are targeted to and retained in the IC, the compartment from which the virus acquires its membranes. Furthermore, a recent study on the entry of both the IMV and extracellular enveloped virus (EEV) suggests that these viruses do not enter by a simple fusion mechanism, consistent with the idea that both are surrounded by more than one lipid bilayer.     

Does the regulation of intracellular protein degradation require protein synthesis?

Temperature-sensitive mutants of mammalian cells were used to show that regulation of protein degradation occurs in the absence of protein synthesis.