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Current Opinion in Genetics & Development

Anant A Agrawal, Lihua Yu, Peter G Smith, Silvia Buonamici
Recently splicing has been recognized as a key pathway in cancer. Although aberrant splicing has been shown to be a consequence of mutations or the abnormal expression of splicing factors (trans-effect changes) or mutations in the splicing sequences (cis-effect mutations), the connections between aberrant splicing and cancer initiation or progression are still not well understood. Here we review the mutational landscape of splicing factors in cancer and associated splicing consequences, along with the most important examples of the therapeutic approaches targeting the spliceosome currently being investigated in oncology...
November 11, 2017: Current Opinion in Genetics & Development
Clara L Kielkopf
Pre-mRNA splicing factors recognize consensus signals within preliminary transcripts, and as cogs of the spliceosome machine, orchestrate the excision and rejoining of pre-mRNA regions for gene expression. Large-scale sequencing has demonstrated that mutations in key genes encoding pre-mRNA splicing factors are common among myeloid neoplasms and also occur in a variety of other cancers. This revelation offers new therapeutic opportunities to target pre-mRNA splicing vulnerabilities in hematologic and other malignancies...
November 9, 2017: Current Opinion in Genetics & Development
Xiaoyan Xu, Yumeng Wang, Han Liang
Adenosine-to-inosine (A-to-I) RNA editing is the most common type of post-transcriptional nucleotide modification in humans, which is catalyzed in ADAR enzymes. Recent genomic studies have revealed thousands of altered RNA editing events in various cancer tissues, leading to diverse functional consequences. A critical role of individual A-to-I RNA editing events in cancer has been reported. Here, we review the current state of our knowledge on key A-to-I RNA editing events in coding and non-coding regions for their roles in cancer development and discuss their potential clinical utility...
November 8, 2017: Current Opinion in Genetics & Development
Maximilian W Popp, Lynne E Maquat
Nonsense-mediated mRNA decay (NMD) is a conserved mRNA surveillance pathway that cells use to ensure the quality of transcripts and to fine-tune transcript abundance. The role of NMD in cancer development is complex. In some cases, tumors have exploited NMD to downregulate gene expression by apparently selecting for mutations causing destruction of key tumor-suppressor mRNAs. In other cases, tumors adjust NMD activity to adapt to their microenvironment. Understanding how particular tumors exploit NMD for their benefit may augment the development of new therapeutic interventions...
November 7, 2017: Current Opinion in Genetics & Development
Alexander D Johnson
The binding of transcription regulators to cis-regulatory sequences is a key step through which all cells regulate expression of their genes. Due to gains and losses of cis-regulatory sequences and changes in the transcription regulators themselves, the binding connections between regulators and their target genes rapidly change over evolutionary time and constitute a major source of biological novelty. This review covers recent work, carried out in a wide range of species, that addresses the overall extent of these evolutionary changes, their consequences, and some of the molecular mechanisms that lie behind them...
November 7, 2017: Current Opinion in Genetics & Development
Frances E Hauser, Belinda Sw Chang
Sensory systems provide valuable insight into the evolution of molecular mechanisms underlying organismal anatomy, physiology, and behaviour. Visual pigments, which mediate the first step in visual transduction, offer a unique window into the relationship between molecular variation and visual performance, and enhance our understanding of how ecology, life history, and physiology may shape genetic variation across a variety of organisms. Here we review recent work investigating vertebrate visual pigments from a number of perspectives...
November 2, 2017: Current Opinion in Genetics & Development
Zi Li, Fujun Qin, Hui Li
Chimeric RNAs have been believed to be solely produced by gene fusions resulting from chromosomal rearrangement, thus unique features of cancer. Detected chimeric RNAs have also been viewed as surrogates for the presence of gene fusions. However, more and more research has demonstrated that chimeric RNAs in general are not a hallmark of cancer, but rather widely present in non-cancerous cells and tissues. At the same time, they may be produced by other mechanisms other than chromosomal rearrangement. The field of non-canonical chimeric RNAs is still in its infancy, with many challenges ahead, including the lack of a unified terminology...
October 31, 2017: Current Opinion in Genetics & Development
Robert F Harvey, Anne E Willis
The processes by which the canonical protein synthesis machinery is modified by environmental stresses to allow healthy cells to respond to external conditions to maintain homeostasis, are frequently hijacked by tumour cells to enhance their survival. Two major stress response pathways that play a major role in this regard are the unfolded protein response (UPR) and the DNA damage response (DDR). Recent data have shown that key proteins which coordinate post-transcriptional control, and which are regulated by signalling through the UPR and DDR, are upregulated in cancers and that targeting these proteins/pathways will provide new therapeutic avenues for cancer treatments...
October 28, 2017: Current Opinion in Genetics & Development
Xosé R Bustelo, Mercedes Dosil
Increasing evidence suggests that alterations in ribosome biogenesis (RiBi) confer competitive advantages to cancer cells. This has led to the discovery of regulatory layers mediated by signaling proteins, oncoproteins, and tumor suppressors whose deregulation leads to increased RiBi rates in cancer cells. In addition to boosting protein synthesis, these alterations probably contribute to shape the protumorigenic proteome of cancer cells. Mutations negatively affecting RiBi are also unexpectedly found in some spontaneous and ribosomopathy-associated tumors...
October 26, 2017: Current Opinion in Genetics & Development
Zahava Siegfried, Rotem Karni
One of the major challenges in cancer treatment today is that many patients develop resistance to the therapeutic agents, resulting in treatment failure. Alternative splicing can significantly alter the coding region of drug targets. Here, we highlight several reports that provide key examples of alternative splicing events that occur in various cancers and play a role in resistance to cancer therapy. These examples present prime targets for future study and development of splicing modulation therapy. Modulation of alternative splicing has recently been approved as treatment for several diseases, although not yet for cancer...
October 25, 2017: Current Opinion in Genetics & Development
Paul B Rainey, Philippe Remigi, Andrew D Farr, Peter A Lind
Over the last two decades interest in direct realisation of evolutionary process and the possibilities presented by real time evolution experiments with microbes have escalated. Long-term selection experiments with bacteria have made increasingly transparent the process of evolution by natural selection. In this short article we consider what next for the field and do so by highlighting two areas of interest: the genotype-to-phenotype map and the constraints it imposes on evolution, and studies on major evolutionary transitions and in particular the importance of selection working over more than one timescale...
October 20, 2017: Current Opinion in Genetics & Development
Xiaowen Hu, Anil K Sood, Chi V Dang, Lin Zhang
Sequencing technology has facilitated a new era of cancer research, especially in cancer genomics. Using next-generation sequencing, thousands of long noncoding RNAs (lncRNAs) have been identified as abnormally altered in the cancer genome or differentially expressed in tumor tissues. These lncRNAs are associated with imbalanced gene regulation and aberrant biological processes that contribute to malignant transformation. The functions and therapeutic potential of cancer-related lncRNAs have attracted considerable interest in the past few years...
October 17, 2017: Current Opinion in Genetics & Development
Xiaolan Deng, Rui Su, Xuesong Feng, Minjie Wei, Jianjun Chen
As the most abundant internal modification in eukaryotic messenger RNAs identified, N(6)-methyladenosine (m(6)A) has been shown recently to play essential roles in various normal bioprocesses. Evidence is emerging that m(6)A modification and its regulatory proteins also play critical roles in various cancers including leukemia, brain tumor, breast cancer and lung cancer, etc. For instance, FTO, the first m(6)A demethylase identified, has been reported recently to play an oncogenic role in leukemia and glioblastoma...
October 14, 2017: Current Opinion in Genetics & Development
Justin Crocker, Garth R Ilsley
Transcriptional enhancers specify the precise time, level, and location of gene expression. Disentangling and characterizing the components of enhancer activity in multicellular eukaryotic development has proven challenging because enhancers contain activator and repressor binding sites for multiple factors that each exert nuanced, context-dependent control of enhancer activity. Recent advances in synthetic biology provide an almost unlimited ability to create and modify regulatory elements and networks, offering unprecedented power to study gene regulation...
September 29, 2017: Current Opinion in Genetics & Development
Jennifer J Wernegreen
Phylogenetically independent bacterial lineages have undergone a profound lifestyle shift: from a free-living to obligately host-associated existence. Among these lineages, intracellular bacterial mutualists of insects are among the most intimate, constrained symbioses known. These obligate endosymbionts exhibit severe gene loss and apparent genome deterioration. Evolutionary theory provides a basis to link their unusual genomic features with shifts in fundamental mechanisms - selection, genetic drift, mutation, and recombination...
September 18, 2017: Current Opinion in Genetics & Development
Edward C Schrom, Andrea L Graham
Over recent years, extensive phenotypic variability and plasticity have been revealed among the T-helper cells of the mammalian adaptive immune system, even within clonal lineages of identical antigen specificity. This challenges the conventional view that T-helper cells assort into functionally distinct subsets following differential instruction by the innate immune system. We argue that the adaptive value of coping with uncertainty can reconcile the 'instructed subset' framework with T-helper variability and plasticity...
September 16, 2017: Current Opinion in Genetics & Development
Simon H Martin, Chris D Jiggins
Introgression, the transfer of genetic material between species through hybridisation, occurs in many taxa and has important consequences. Genomic studies allow us to characterise the landscape of introgression across the genome, shedding light on both its adaptive benefits and the incompatibilities that help to maintain species barriers. Studies taking a genome-wide view suggest that adaptive introgression may be common, but that introgressed variation between many species is selected against throughout much of the genome...
September 15, 2017: Current Opinion in Genetics & Development
Jenny Tung, Luis B Barreiro
Genome-wide data on genetic variation are now available for multiple primate species and populations, facilitating analyses of evolutionary history within and across taxa. One emerging theme from these studies involves the central role of admixture. Genomic data sets indicate that both ancient gene flow following initial taxonomic divergence and ongoing gene flow at current species boundaries are common. These findings are of particular interest given evidence for a complex history of admixture in our own lineage, including examples of ecologically driven adaptive introgression...
September 15, 2017: Current Opinion in Genetics & Development
June B Nasrallah
Flowering plants have evolved diverse mechanisms that promote outcrossing. The most widespread of these outbreeding devices are self-incompatibility systems, the highly selective prefertilization mating barriers that prevent self-fertilization by disrupting pollen-pistil interactions. Despite the advantages of outcrossing, loss of self-incompatibility has occurred repeatedly in many plant families. In the mustard family, the highly polymorphic receptors and ligands that mediate the recognition and inhibition of self-pollen in self-incompatibility have been characterized and the 3D structure of the receptor-ligand complex has been solved...
September 12, 2017: Current Opinion in Genetics & Development
Téo Fournier, Joseph Schacherer
Dissecting the genetic basis of natural phenotypic variation is a major goal in biology. We know that most traits are strongly heritable. However, their genetic architecture is a long-standing question, which is unfortunately confounded by the lack of complete knowledge of the genetic components as well as their phenotypic effect in a specific genetic background. Many genetic variants are known to affect phenotypes but the same functional variant can have a different effect on the phenotype in different individuals of the same species...
September 12, 2017: Current Opinion in Genetics & Development
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