Seminars in cell & developmental biology最新文献

The emergence of therapeutic resistance remains a formidable barrier to durable responses by cancer patients and is a major cause of cancer-related deaths. It is increasingly recognized that non-genetic mechanisms of acquired resistance are important in many cancers. These mechanisms of resistance rely on inherent cellular plasticity where cancer cells can switch between multiple phenotypic states without genetic alterations, providing a dynamic, reversible resistance landscape. Such mechanisms underlie the generation of drug-tolerant persister (DTP) cells, a subpopulation of tumour cells that contributes to heterogeneity within tumours and that supports therapeutic resistance. In this review, we provide an overview of the major features of DTP cells, focusing on phenotypic and metabolic plasticity as two key drivers of tolerance and persistence. We discuss the link between DTP cell plasticity and the potential vulnerability of these cells to ferroptosis. We also discuss the relationship between DTP cells and cells that survive the induction of apoptosis, a process termed anastasis, and discuss the properties of such cells in the context of increased metastatic potential and sensitivity to cell death mechanisms such as ferroptosis.

Maintenance of genome stability relies on functional centromeres for correct chromosome segregation and faithful inheritance of the genetic information. The human centromere is the primary constriction within mitotic chromosomes made up of repetitive alpha-satellite DNA hierarchically organized in megabase-long arrays of near-identical higher order repeats (HORs). Centromeres are epigenetically specified by the presence of the centromere-specific histone H3 variant, CENP-A, which enables the assembly of the kinetochore for microtubule attachment. Notably, centromeric DNA is faithfully inherited as intact haplotypes from the parents to the offspring without intervening recombination, yet, outside of meiosis, centromeres are akin to common fragile sites (CFSs), manifesting crossing-overs and ongoing sequence instability. Consequences of DNA changes within the centromere are just starting to emerge, with unclear effects on intra- and inter-generational inheritance driven by centromere’s essential role in kinetochore assembly. Here, we review evidence of meiotic selection operating to mitigate centromere drive, as well as recent reports on centromere damage, recombination and repair during the mitotic cell division. We propose an antagonistic pleiotropy interpretation to reconcile centromere DNA instability as both driver of aneuploidy that underlies degenerative diseases, while also potentially necessary for the maintenance of homogenized HORs for centromere function. We attempt to provide a framework for this conceptual leap taking into consideration the structural interface of centromere-kinetochore interaction and present case scenarios for its malfunctioning. Finally, we offer an integrated working model to connect DNA instability, chromatin, and structural changes with functional consequences on chromosome integrity.

If mitochondria are the powerhouses of the cell, then mitochondrial dynamics are the power grid that regulates how that energy output is directed and maintained in response to unique physiological demands. Fission and fusion dynamics are highly regulated processes that fine-tune the mitochondrial networks of cells to enable appropriate responses to intrinsic and extrinsic stimuli, thereby maintaining cellular and organismal homeostasis. These dynamics shape many aspects of an organism’s healthspan including development, longevity, stress resistance, immunity, and response to disease. In this review, we discuss the latest findings regarding the mechanisms and roles of mitochondrial dynamics by focussing on the nematode Caenorhabditis elegans. Whole live-animal studies in C. elegans have enabled a true organismal-level understanding of the impact that mitochondrial dynamics play in homeostasis over a lifetime.

Centromeres are large structural regions in the genomic DNA, which are essential for accurately transmitting a complete set of chromosomes to daughter cells during cell division. In humans, centromeres consist of highly repetitive α-satellite DNA sequences and unique epigenetic components, forming large proteinaceous structures required for chromosome segregation. Despite their biological importance, there is a growing body of evidence for centromere breakage across the cell cycle, including periods of quiescence. In this review, we provide an up-to-date examination of the distinct centromere environments at different stages of the cell cycle, highlighting their plausible contribution to centromere breakage. Additionally, we explore the implications of these breaks on centromere function, both in terms of negative consequences and potential positive effects.

Abundant tandemly repeated satellite DNA is present in most eukaryotic genomes. Previous limitations including a pervasive view that it was uninteresting junk DNA, combined with challenges in studying it, are starting to dissolve - and recent studies have found important functions for satellite DNAs. The observed rapid evolution and implied instability of satellite DNA now has important significance for their functions and maintenance within the genome. In this review, we discuss the processes that lead to satellite DNA copy number instability, and the importance of mechanisms to manage the potential negative effects of instability. Satellite DNA is vulnerable to challenges during replication and repair, since it forms difficult-to-process secondary structures and its homology within tandem arrays can result in various types of recombination. Satellite DNA instability may be managed by DNA or chromatin-binding proteins ensuring proper nuclear localization and repair, or by proteins that process aberrant structures that satellite DNAs tend to form. We also discuss the pattern of satellite DNA mutations from recent mutation accumulation (MA) studies that have tracked changes in satellite DNA for up to 1000 generations with minimal selection. Finally, we highlight examples of satellite evolution from studies that have characterized satellites across millions of years of Drosophila fruit fly evolution, and discuss possible ways that selection might act on the satellite DNA composition.

Satellite DNA sequences are an integral part of centromeres, regions critical for faithful segregation of chromosomes during cell division. Because of their complex repetitive structure, satellite DNA may act as a barrier to DNA replication and other DNA based transactions ultimately resulting in chromosome breakage. Over the past two decades, several DNA repair proteins have been shown to bind and function at centromeres. While the importance of these repair factors is highlighted by various structural and numerical chromosome aberrations resulting from their inactivation, their roles in helping to maintain genome stability by solving the intrinsic difficulties of satellite DNA replication or promoting their repair are just starting to emerge. In this review, we summarize the current knowledge on the role of DNA repair and DNA damage response proteins in maintaining the structure and function of centromeres in different contexts. We also report the recent connection between the roles of specific DNA repair factors at these genomic loci with age-related increase of chromosomal instability under physiological and pathological conditions.

Oomycete plant pathogens, such as Phytophthora and Pythium species produce motile dispersal agents called zoospores that actively target host plants. Zoospores are exceptional in their ability to display taxis to chemical, electrical and physical cues to navigate the phyllosphere and reach stomata, wound sites and roots. Many components of root exudates have been shown attractive or repulsive to zoospores. Although some components possess very strong attractiveness, it seems that especially the mix of components exuded by the primary host is most attractive to zoospores. Zoospores actively approach attractants with swimming behaviour reminiscent of other microswimmers. To achieve a unified description of zoospore behaviour when sensing an attractant, we propose the following terms for the successive stages of the homing response: reorientation, approaching, retention and settling. How zoospores sense and process attractants is poorly understood but likely involves signal perception via cell surface receptors. Since zoospores are important for infection, undermining their activity by luring attractants or blocking receptors seem promising strategies for disease control.

Downy mildews are obligate oomycete pathogens that attack a wide range of plants and can cause significant economic impacts on commercial crops and ornamental plants. Traditionally, downy mildew disease control relied on an integrated strategies, that incorporate cultural practices, deployment of resistant cultivars, crop rotation, application of contact and systemic pesticides, and biopesticides. Recent advances in genomics provided data that significantly advanced understanding of downy mildew evolution, taxonomy and classification. In addition, downy mildew genomics also revealed that these obligate oomycetes have reduced numbers of virulence factor genes in comparison to hemibiotrophic and necrotrophic oomycetes. However, downy mildews do deploy significant arrays of virulence proteins, including so-called RXLR proteins that promote virulence or are recognized as avirulence factors. Pathogenomics are being applied to downy mildew population studies to determine the genetic diversity within the downy mildew populations and manage disease by selection of appropriate varieties and management strategies. Genome editing technologies have been used to manipulate host disease susceptibility genes in different plants including grapevine and sweet basil and thereby provide new soucres of resistance genes against downy mildews. Previously, it has proved difficult to transform and manipulate downy mildews because of their obligate lifestyle. However, recent exploitation of RNA interference machinery through Host-Induced Gene Silencing (HIGS) and Spray-Induced Gene Silencing (SIGS) indicate that functional genomics in downy mildews is now possible. Altogether, these breakthrough technologies and attendant fundamental understanding will advance our ability to mitigate downy mildew diseases.

Plant diseases caused by soilborne pathogens are a major limiting factor in crop production. Bacterial wilt disease, caused by soilborne bacteria in the Ralstonia solanacearum Species Complex (Ralstonia), results in significant crop loss throughout the world. Ralstonia invades root systems and colonizes plant xylem, changing plant physiology and ultimately causing plant wilting in susceptible varieties. Elucidating how Ralstonia invades and colonizes plants is central to developing strategies for crop protection. Here we review Ralstonia pathogenesis from root detection and attachment, early root colonization, xylem invasion and subsequent wilting. We focus primarily on studies in tomato from the last 5–10 years. Recent work has identified elegant mechanisms Ralstonia uses to adapt to the plant xylem, and has discovered new genes that function in Ralstonia fitness in planta. A picture is emerging of an amazingly versatile pathogen that uses multiple strategies to make its surrounding environment more hospitable and can adapt to new environments.

Regulation of protein synthesis is a strong determinant of potyviral pathogenicity. The Potyviridae family is the largest family of plant-infecting positive sense RNA viruses. Similar to the animal-infecting Picornaviridae family, the potyviral RNA genome lacks a 5′ cap, and instead has a viral protein (VPg) linked to its 5′ end. Potyviral genomes are mainly translated into one large polyprotein relying on a single translation event to express all their protein repertoire. In the absence of the 5′ cap, the Potyviridae family depends on cis-acting elements in their 5′ untranslated regions (UTR) to recruit the translation machinery. In this review, we summarize the diverse 5′UTR-driven, cap-independent translation mechanisms employed by the Potyviridae family including scanning-dependent mechanism, internal initiation, and the stimulatory role of the VPg. These mechanisms have direct implications on potyviral pathogenicity, including host range specificity and resistance. Finally, we discuss how these viral strategies could not only inform new avenues for engineering and/or breeding for crop resistance but would also provide opportunities for the development of biotechnological tools for large-scale protein production in plant systems.