Current Opinion in Genetics & Development | Page 2

Veronica Cherdyntseva, Sarantis Gagos
At the crossroads of DNA damage repair and genomic instability, telomere research significantly expands our knowledge on fundamental mechanisms involved in cancer initiation and progression, pledging novel tools for targeted and universal onco-therapies. Molecular cytogenetics through the application of a battery of fluorescent hybridization technologies plays an important role toward understanding telomere homeostasis. Herein, we review distinct molecular cytogenetic phenotypes associated with telomere repair, functionality, and elongation...
March 16, 2020: Current Opinion in Genetics & Development
Yue Shao, Jianping Fu
Study of early human embryo development is essential for advancing reproductive and regenerative medicine. Traditional human embryological studies rely on embryonic tissue specimens, which are difficult to acquire due to technical challenges and ethical restrictions. The availability of human stem cells with developmental potentials comparable to pre-implantation and peri-implantation human embryonic and extraembryonic cells, together with properly engineered in vitro culture environments, allow for the first time researchers to generate self-organized multicellular structures in vitro that mimic the structural and molecular features of their in vivo counterparts...
March 12, 2020: Current Opinion in Genetics & Development
Susanna Stroik, Eric A Hendrickson
Telomere fusions inevitably arise as a cell's last-ditch effort to protect exposed chromosomal ends when telomeres are lost due to aging-associated erosion, breakage, failed replication, or a plethora of other cellular mistakes. Fusion of an exposed chromosomal end to another telomere presumably presents a superficially attractive option to the cell as opposed to the alternative of the impending degradation of the unprotected chromosomal terminus. However, when allowed to progress to mitosis these fusion events subsequently foster non-disjunction or bridge:breakage events - both of which drive highly pathogenic genomic instability and additional chromosomal translocations...
March 12, 2020: Current Opinion in Genetics & Development
Alessandro Cicconi, Sandy Chang
Telomeres are G-rich repetitive sequences that are difficult to replicate, resulting in increased replication stress that can threaten genome stability. Shelterin protects telomeres from engaging in aberrant DNA repair and dictates the choice of DNA repair pathway at dysfunctional telomeres. Recently, shelterin has been shown to participate in telomere replication. Here we review the most recent discoveries documenting the mechanisms by which shelterin represses DNA repair pathways at telomeres while assisting its replication...
March 12, 2020: Current Opinion in Genetics & Development
Marlis Denk-Lobnig, Adam C Martin
Folding is an important way by which epithelia are sculpted into three-dimensional shapes during development. Recent studies have integrated quantitative image analysis and physical modeling to uncover contributing mechanisms. It is becoming clear that folding processes often employ multiple mechanisms of force generation. Here, we review divergent modes of epithelial folding. We argue that, in many cases, several mechanisms interact at different time-scales and length-scales to generate a fold. In other cases, very similar folds are generated by different folding mechanisms...
March 11, 2020: Current Opinion in Genetics & Development
Christopher P Nelson, Veryan Codd
The relationship of telomere length with cancer risk has been the source of much debate within epidemiological studies, which have produced inconsistent finding both between and within different cancer types. Over recent years, genome-wide association studies of increasing size have identified variants that determine human telomere length. These variants have subsequently been utilised as instrumental variables in Mendelian randomisation based studies, allowing the investigation of potential causal relationships between telomere length and cancer...
March 11, 2020: Current Opinion in Genetics & Development
Franziska K Lorbeer, Dirk Hockemeyer
Telomerase regulation and telomere shortening act as a strong tumor suppressor mechanism in human somatic cells. Point mutations in the promoter of telomerase reverse transcriptase (TERT) are the most frequent non-coding mutation in cancer. These TERT promoter mutations (TPMs) create de novo ETS factor binding sites upstream of the start codon of the gene, which can be bound by different ETS factors. TPMs can occur early during tumorigenesis and are thought to be among the first mutations in melanoma, glioblastoma and hepatocellular carcinoma...
March 9, 2020: Current Opinion in Genetics & Development
Yi Gong, Amanda J Stock, Yie Liu
The discovery that rare POT1 variants are associated with extremely long telomeres and increased cancer predisposition has provided a framework to revisit the relationship between telomere length and cancer development. Telomere shortening is linked with increased risk for cancer. However, over the past decade, there is increasing evidence to show that extremely long telomeres caused by mutations in shelterin components (POT1, TPP1, and RAP1) also display an increased risk of cancer. Here, we will review current knowledge on germline mutations of POT1 identified from cancer-prone families...
March 7, 2020: Current Opinion in Genetics & Development
Sally M Dewhurst
In the early stages of carcinogenesis cells confront two key suppressive checkpoints; senescence and telomere crisis. Telomere crisis is characterized by massive chromosomal instability and cell death. The genetic instability initiated during crisis leaves detectable scars on cancer genomes, the full scope of which is only just beginning to be appreciated. In particular, the dramatic genome reshuffling phenomenon chromothripsis has been mechanistically linked to the resolution of DNA bridges formed by dicentric chromosomes, and by the shattering of DNA inside micronuclei...
March 6, 2020: Current Opinion in Genetics & Development
Mingyuan Zhu, Adrienne Hk Roeder
Plant are better engineers than us. They reproducibly create new organs while we are still far from being able to engineer plant morphogenesis. It is challenging to understand plant morphogenesis due to its complexity. Complex intersecting regulatory networks often mask general principles. Cells and molecular regulators typically behave variably yet the plant uses these inputs to achieve robust outcomes. Regulatory networks often act in the non-linear range near tipping points such that small stochastic variations are used to make important developmental decisions...
March 5, 2020: Current Opinion in Genetics & Development
Shigeo Hayashi, Yosuke Ogura
Receptor tyrosine kinases (RTK) are transmembrane kinases that receive signals for intercellular communication to help organize body plan and sustain tissue homeostasis. These signals converge into the major signaling module of ERK, which transduces signals to the cytoplasm and nucleus. How this module responds to multiple RTK signals, and specifies unique outcomes in each cell, is still poorly understood. Recent technological advances in the quantitative imaging of ERK activity and its manipulation have yielded significant information on the cellular logic behind ERK activation and its readout in the context of Drosophila development...
March 4, 2020: Current Opinion in Genetics & Development
Ragini Bhargava, Matthias Fischer, Roderick J O'Sullivan
There is unequivocal evidence that telomeres are crucial for cellular homeostasis and that telomere dysfunction can elicit genome instability and potentially initiate events that culminate in cancer. Mounting evidence points to telomeres having a crucial role in driving local and systemic structural rearrangements that drive cancer. These include the classical 'breakage-fusion-bridge' (BFB) cycles and more recently identified genome re-shaping events like kataegis and chromothripsis. In this brief review, we outline the established and most recent advances describing the roles that telomere dysfunction has in the origin of these catastrophic genome rearrangements...
March 4, 2020: Current Opinion in Genetics & Development
Alexander P Sobinoff, Hilda A Pickett
Telomere maintenance is essential for the continued proliferation of mitotically active cells. Alternative Lengthening of Telomeres (ALT) is a recombination-dependent pathway of telomere maintenance analogous to break-induced replication (BIR) [1] that becomes activated in approximately 10-15% of human cancers. ALT is prevalent in tumours of mesenchymal or neuroepithelial origin, and typically confers a poor prognosis. The aggressiveness and lack of effective strategies to treat these cancers make the ALT pathway a compelling potential therapeutic target to prevent tumour formation and/or the appearance of secondary malignancies after conventional chemotherapy [2]...
February 28, 2020: Current Opinion in Genetics & Development
Donghyun D Lee, Martin Komosa, Nuno Miguel Nunes, Uri Tabori
Telomere maintenance is a hallmark of human cancer that enables replicative immortality. Most cancer cells acquire telomere maintenance by telomerase activation through expression of telomerase reverse transcriptase (TERT), a rate-limiting component of the telomerase holoenzyme. Although multiple cancer-specific genetic alterations such as gain of TERT copy number and recurrent TERT promoter mutations (TPM) have been identified, the majority of cancers still express TERT via unknown mechanisms. In the last decade, DNA methylation of the TERT promoter emerged as a putative epigenetic regulatory mechanism of telomerase activation in cancer...
February 27, 2020: Current Opinion in Genetics & Development
Eloïse Claude, Anabelle Decottignies
Cancer cells acquire replicative immortality by activating a telomere maintenance mechanism (TMM), either the telomerase or the Alternative Lengthening of Telomeres (ALT) mechanism. ALT is frequently activated in tumors derived from mesenchymal cells, which are more frequent in childhood cancers. Recent studies showed that, occasionally, cancer cells can arise without any TMM activation. Here, we discuss the challenge in assessing which TMM is activated in tumors. We also evaluate the prevalence of ALT mechanism in pediatric cancers and review the associated survival prognosis in different tumor types...
February 27, 2020: Current Opinion in Genetics & Development
Shir Toubiana, Sara Selig
Subtelomeres are the regions at chromosome ends, immediately adjacent to the terminal telomeric repeats. The majority of human subtelomeres are CpG-rich in their distal two kilobases, and are methylated during early embryonic development by the de novo DNA methyltransferase DNMT3B. The biological relevance of subtelomeric DNA methylation is highlighted by the presence of promoters for the long non-coding TERRA transcripts in these CpG-rich regions. Indeed, deviant subtelomeric methylation has been linked with abnormal telomeric phenotypes, as most strikingly found in ICF syndrome...
February 25, 2020: Current Opinion in Genetics & Development
Ghislain Gillard, Katja Röper
Morphogenesis is an essential process by which a given tissue, organ or organism acquires its final shape. A select number of mechanisms are used in order to drive epithelial morphogenesis, including cell shape changes as well as cell death or cell division. A cell's shape results from the combination of intrinsic properties of the actomyosin and microtubule (MTs) cytoskeletons, and extrinsic properties due to physical interactions with the neighbouring environment. While we now have a good understanding of the genetic pathways and some of the signalling pathways controlling cell shape changes, the mechanical properties of cells and their role in morphogenesis remain largely unexplored...
February 21, 2020: Current Opinion in Genetics & Development
Chris Pepper, Kevin Norris, Christopher Fegan
Cancer remains one of the leading causes of death in the developed world and despite impressive advances in therapeutic modalities, only a small subset of patients are currently cured. The underlying genetic heterogeneity of cancers clearly plays a crucial role in determining both the clinical course of individual pathologies and their responses to standard treatments. Although every tumour is to some extent distinct, there are recurrent features of cancers that can be exploited as therapeutic targets and as prognostic and predictive biomarkers; one such attribute is telomere length...
February 2020: Current Opinion in Genetics & Development
Hanzhi Zhao, Ying Jin
No abstract text is available yet for this article.
January 31, 2020: Current Opinion in Genetics & Development
Edgar M Medina, Evan Walsh, Nicolas E Buchler
Fungi are found in diverse ecological niches as primary decomposers, mutualists, or parasites of plants and animals. Although animals and fungi share a common ancestor, fungi dramatically diversified their life cycle, cell biology, and metabolism as they evolved and colonized new niches. This review focuses on a family of fungal transcription factors (Swi4/Mbp1, APSES, Xbp1, Bqt4) derived from the lateral gene transfer of a KilA-N domain commonly found in prokaryotic and eukaryotic DNA viruses. These virus-derived fungal regulators play central roles in cell cycle, morphogenesis, sexual differentiation, and quiescence...
October 7, 2019: Current Opinion in Genetics & Development
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