Translesion DNA polymerases in eukaryotes: what makes them tick?

Life as we know it, simply would not exist without DNA replication. All living organisms utilize a complex machinery to duplicate their genomes and the central role in this machinery belongs to replicative DNA polymerases, enzymes that are specifically designed to copy DNA. “Hassle-free” DNA duplication exists only in an ideal world, while in real life, it is constantly threatened by a myriad of diverse challenges. Among the most pressing obstacles that replicative polymerases often cannot overcome by themselves are lesions that distort the structure of DNA. Despite elaborate systems that cells utilize to cleanse their genomes of damaged DNA, repair is often incomplete. The persistence of DNA lesions obstructing the cellular replicases can have deleterious consequences. One of the mechanisms allowing cells to complete replication is “Translesion DNA Synthesis (TLS)”. TLS is intrinsically error-prone, but apparently, the potential downside of increased mutagenesis is a healthier outcome for the cell than incomplete replication. Although most of the currently identified eukaryotic DNA polymerases have been implicated in TLS, the best characterized are those belonging to the “Y-family” of DNA polymerases (pols η, ι, κ and Rev1), which are thought to play major roles in the TLS of persisting DNA lesions in coordination with the B-family polymerase, pol ζ. In this review, we summarize the unique features of these DNA polymerases by mainly focusing on their biochemical and structural characteristics, as well as potential protein–protein interactions with other critical factors affecting TLS regulation.     

Bio-switches: what makes them robust?

Ideas of how a system of interacting enzymes can act as a switch are based on the concept of bistability of a biochemical network. This means that, because of the very structure of a signaling pathway, the system can be in one of two stable steady states: active or inactive. Switching from one state to another may then occur in response to external stimuli or as a result of internal development. However, the bistability of a biochemical network might not be robust enough to be the sole mechanism behind bio-switching. On the basis of recent experimental data on the cell-cycle G2/M transition during starfish oocyte meiotic maturation, it is shown that cooperative phenomena--such as phase changes associated with clustering, dissolution of aggregates and so on--may play central roles in providing a decisive and irreversible transition.     

Integrin-mediated type IV secretion by Helicobacter: what makes it tick?

Helicobacter pylori (Hp) employs a multi-component type IV secretion system (T4SS) to secrete the effector protein CagA into the cytosol of infected host cells. A longstanding challenge has been to identify the host cell receptor(s) involved. Two recent studies have independently unveiled human β(1) integrin as the receptor but are divided over which T4SS proteins bind to β(1) integrin. Here we revisit the two models in light of previous findings and recent progress in the field. More concerted efforts are required to fully understand the complex T4SS mechanisms that underpin Hp pathogenesis.     

Circadian clocks: A cry in the dark?

Cryptochrome proteins are key components of the circadian systems of both Drosophila and mammals. In Drosophila, they appear to be responsible for the entrainment of the circadian clock by the light-dark cycle, while in mammals they perform an important role in rhythm generation itself.     

Vav1 mutations: What makes them oncogenic?

Vav1 is physiologically active as a GDP/GTP nucleotide exchange factor (GEF) in the hematopoietic system. Its wild-type form was recently implicated in mammalian malignancies of hematologic and non-hematologic tissue origins. Moreover, it was recently identified as a mutated gene in human cancers of various origins. In this review we focus on the functional activities of several of the Vav1 mutants analyzed for their tumorigenic properties. We also discuss the relationship of the tested biochemical properties of Vav1 mutants, E59K, D517E and L801P, to their computer-based predicted properties. These comparisons further enhance the need for integration of computation-based structural analyses with experimental data in order to fully appreciate the activity of mutant proteins. Our comprehensive evaluation supports the classification of Vav1 as a bona fide oncogene in human cancers.     

Centromeric chromatin: what makes it unique?

Centromeres represent the final frontier of eukaryotic genomes. Although they are defining features of chromosomes--the points at which spindle microtubules attach--the fundamental features that distinguish them from other parts of the chromosome remain mysterious. The function of centromeres is conserved throughout eukaryotic biology, but their DNA sequences are not. Rather, accumulating evidence favors chromatin-based centromeric identification. To understand how centromeric identity is maintained, researchers have studied DNA-protein interactions at native centromeres and ectopic "neocentromeres". Other studies have taken a comparative approach focusing on centromere-specific proteins, of which mammalian CENP-A and CENP-C are the prototypes. Elucidating the assembly and structure of chromatin at centromeres remain key challenges.     

Batteries: what causes them to fail?

Rechargeable batteries do not die suddenly but gradually get weaker over time. The ability to hold charge diminishes through aging, usage (cycling), handling and environmental conditions. Batteries seem to have their own inherited life span. A fixed replacement plan, in which all batteries are replaced at a certain age, does not work well. Rather, each battery should periodically be analyzed and only those replaced whose capacity drops below an acceptable performance threshold. Implementing such a maintenance program reduces unexpected downtime caused by weak batteries and saves money. Unexpected downtime due to failing batteries can cause tense moments for the equipment operator. Some people may even seek legal compensation for personal damages suffered by a failing battery.     

Application of hairy roots for phytoremediation: what makes them an interesting tool for this purpose?

In recent years, hairy roots (HRs) have been successfully used as research tools for screening the potentialities of different plant species to tolerate, accumulate, and/or remove environmental pollutants, such as PCBs, TNT, pharmaceuticals, textile dyes, phenolics, heavy metals, and radionuclides. This is in part due to several advantages of this plant model system and the fact that roots have evolved specific mechanisms to deal with pollutants because they are the first organs to have contact with them. In addition, by using HRs some metabolic pathways and enzymatic catalyzed reactions involved in pollutants detoxification can be elucidated as well as the mechanisms of uptake, transformation, conjugation, and compartmentation of pollutants in vacuoles and/or cell walls, which are important detoxification sites in plants. Plant roots also stimulate the degradation of contaminants by the release of root exudates and oxido-reductive enzymes, such as peroxidases (Px) and laccases, that are associated with the removal of some organic pollutants. HRs are also considered good alternatives as enzyme sources for remediation purposes. Furthermore, application of genetic engineering methods and development of microbe-assisted phytoremediation are feasible strategies to enhance plant capabilities to tolerate, accumulate, and/or metabolize pollutants and, hence, to create or find an appropriate plant system for environmental cleanup. The present review highlights current knowledge, recent progress, areas which need to be explored, and future perspectives related to the application and improvement of the efficiency of HRs for phytoremediation research.     

Statins in cardiometabolic disease: what makes pitavastatin different?

The term cardiometabolic disease encompasses a range of lifestyle-related conditions, including Metabolic syndrome (MetS) and type 2 diabetes (T2D), that are characterized by different combinations of cardiovascular (CV) risk factors, including dyslipidemia, abdominal obesity, hypertension, hyperglycemia/insulin resistance, and vascular inflammation. These risk factors individually and interdependently increase the risk of CV and cerebrovascular events, and represent one of the biggest health challenges worldwide today. CV diseases account for almost 50% of all deaths in Europe and around 30% of all deaths worldwide. Furthermore, the risk of CV death is increased twofold to fourfold in people with T2D. Whilst the clinical management of CV disease has improved in Western Europe, the pandemic of obesity and T2D reduces the impact of these gains. This, together with the growing, aging population, means the number of CV deaths is predicted to increase from 17.1 million worldwide in 2004 to 23.6 million in 2030. The recommended treatment for MetS is lifestyle change followed by treatment for the individual risk factors. Numerous studies have shown that lowering low-density lipoprotein-cholesterol (LDL-C) levels using statins can significantly reduce CV risk in people with and without T2D or MetS. However, the risk of major vascular events in those attaining the maximum levels of LDL-C-reduction is only reduced by around one-third, which leaves substantial residual risk. Recent studies suggest that low high-density lipoprotein-cholesterol (HDL-C) (<1 .0 mmol/l; 40 mg/dl) and high triglyceride levels (≥1.7 mmol/l; 150 mg/dl) are independent risk factors for CV disease and that the relationship between HDL-C and CV risk persists even when on-treatment LDL-C levels are low (<1.7 mmol/l; 70 mg/dl). European guidelines highlight the importance of reducing residual risk by targeting these risk factors in addition to LDL-C. This is particularly important in patients with T2D and MetS because obesity and high levels of glycated hemoglobin are directly related to low levels of HDL-C and high triglyceride. Although most statins have a similar low-density lipoprotein-lowering efficacy, differences in chemical structure and pharmacokinetic profile can lead to variations in pleiotropic effects (for example, high-density lipoprotein-elevating efficacy), adverse event profiles, and drug-drug interactions. The choice of statin should therefore depend on the needs of the individual patient. The following reviews will discuss the potential benefits of pitavastatin versus other statins in the treatment of patients with dyslipidemia and MetS or T2D, focusing on its effects on HDL-C quantity and quality, its potential impact on atherosclerosis and CV risk, and its metabolic characteristics that reduce the risk of drug interactions. Recent controversies surrounding the potentially diabetogenic effects of statins will also be discussed.     

Individual-based modelling in ecology: what makes the difference?

Is individual-based modelling really a new approach in ecology? A large part of the uncertainty surrounding this question is a consequence of imprecisely delimited boundaries between classical and individual-based modelling. Genuine 'individual-based' models describe a population made up of individuals that may differ from one another; they also describe changes in numbers of individuals rather than in the population density, and take resource dynamics explicitly into account. Individual-based models that fulfil these criteria will not characterize ecological systems as 'stable' systems in their ideal form, with equilibrium states represented by points in the phase space.     

Phosphorothioate oligodeoxynucleotides: what is their origin and what is unique about them?

The development of nucleoside phosphorothioates is described in its historical context. Examples of the interaction of phosphorothioate groups, present either in oligodeoxynucleotides or in DNA, with nucleases are presented. The structural features responsible for the resistance of the phosphorothioates toward degradation by nucleases are discussed, as are the possible reasons for the high-affinity interaction of phosphorothioate oligodeoxynucleotides with certain proteins.     

Bone mass increase in puberty: what makes it happen?

It is now thought that the critical property of bone is strength rather than weight, and that control of bone strength is mainly exercised through the effect of the mechanical loads brought to bear on bone. Muscle contraction places the greatest physiological load on bone, and so the strength of bone must be adapted to muscle strength (the functional muscle-bone unit). The Utah paradigm of skeletal physiology [J Hum Biol 1998;10:599-605] provides a model of bone development that describes how bone structure is regulated by local mechanical effects that can be adjusted by the effects of hormones. The DONALD (Dortmund Nutritional and Anthropometric Longitudinally Designed) study analysed the interaction between the muscle and bone systems in males and females before and during puberty. This study found that differences between the genders in bone adaptation during puberty are at least partly driven by the influence of oestrogen in females. Testosterone seems to have no direct relevant effect on bone during puberty, but may be implicated in the greater amount of muscle mass achieved in boys compared with girls.     

Valuable research or short stories: what makes the difference?

Accurate communication of scientific research about biological entities is critically dependent on correct identification and naming of the entities involved. This is not a simple task, particularly in a group such as the Triticeae in which there are still many taxa whose limits are only poorly understood. Even if the names used are appropriate at the time a study is completed, subsequent research may lead to a change in the boundaries of some of the entities involved, and consequently in their nomenclature. These factors make it critically important that the identity of the biological entities studied be documented by the preparation of voucher specimens. Voucher specimens enable others to understand the meaning of the names as used by the authors of the paper and maintain the value of the research, even if the systematic framework prevailing at the time of the research is altered. Failure to make voucher specimens can reduce potentially valuable research reports to nothing more than short stories of questionable credibility or, worse, misleading stories. Examples are provided in which voucher specimens extended the longevity of a paper, and others in which the value of a paper was minimized by the lack of voucher specimens.     

Egg quality in fish: what makes a good egg?

Factors affecting egg quality are determined by the intrinsic properties of the egg itself and the environment in which the egg is fertilized and subsequently incubated. Egg quality in fish is very variable. Some of the factors affecting egg quality in fish are known, but many (probably most) are unknown. Components that do affect egg quality include the endocrine status of the female during the growth of the oocyte in the ovary, the diet of the broodfish, the complement of nutrients deposited into the oocyte, and the physiochemical conditions of the water in which the eggs are subsequently incubated. In captive broodfish, the husbandry practices to which fish are subjected are probably a major contributory factor affecting egg quality. Our knowledge of the genetic influences on egg quality is very limited indeed. We know that parental genes strongly influence both fecundity and egg quality, but almost nothing is known about gene expression and/or mRNA translation in fish oocytes/embryos. This is surprising because the products synthesized in ovoand the mechanisms controlling their expression are likely to play a central role in determining egg quality. The genetic mechanisms underpinning oocyte and embryo growth and development are a priority for research     

What makes us tick? Functional and neural mechanisms of interval timing

Time is a fundamental dimension of life. It is crucial for decisions about quantity, speed of movement and rate of return, as well as for motor control in walking, speech, playing or appreciating music, and participating in sports. Traditionally, the way in which time is perceived, represented and estimated has been explained using a pacemaker-accumulator model that is not only straightforward, but also surprisingly powerful in explaining behavioural and biological data. However, recent advances have challenged this traditional view. It is now proposed that the brain represents time in a distributed manner and tells the time by detecting the coincidental activation of different neural populations.     

Human female meiosis: what makes a good egg go bad?

Critical events of oogenesis occur during three distinct developmental stages: meiotic initiation in the fetal ovary, follicle formation in the perinatal period, and oocyte growth and maturation in the adult. Evidence from studies in humans and mice suggests that the genetic quality of the egg may be influenced by events at each of these stages. Recent experimental studies add additional complexity, suggesting that environmental influences might adversely affect all three stages. Thus, understanding the molecular control of oogenesis during these critical developmental windows will not only contribute to an understanding of human aneuploidy, but also provide a means of assessing potential effects of environmental exposures on human reproductive health.