Showing papers in "Annual Review of Genetics in 2006"
TL;DR: It is argued that although categorizing different D SB repair mechanisms along pathways and subpathways can be conceptually useful, in cells flexible and reversible interactions among DSB repair factors form a web from which a nonpredetermined path to repair for any number of different DNA breaks will emerge.
Abstract: Breaks in both DNA strands are a particularly dangerous threat to genome stability. At a DNA double-strand break (DSB), potentially lost sequence information cannot be recovered from the same DNA molecule. However, simple repair by joining two broken ends, though inherently error prone, is preferable to leaving ends broken and capable of causing genome rearrangements. To avoid DSB-induced genetic disinformation and disruption of vital processes, such as replication and transcription, cells possess robust mechanisms to repair DSBs. Because all breaks are not created equal, the particular repair mechanism used depends largely on what is possible and needed based on the structure of the broken DNA. We argue that although categorizing different DSB repair mechanisms along pathways and subpathways can be conceptually useful, in cells flexible and reversible interactions among DSB repair factors form a web from which a nonpredetermined path to repair for any number of different DNA breaks will emerge.
797 citations
TL;DR: The molecular mechanisms that regulate cell division and endoreduplication are reviewed and the understanding on how the cell cycle is integrated with plant development is discussed.
Abstract: Cell cycle regulation is of pivotal importance for plant growth and development. Although plant cell division shares basic mechanisms with all eukaryotes, plants have evolved novel molecules orchestrating the cell cycle. Some regulatory proteins, such as cyclins and inhibitors of cyclin-dependent kinases, are particularly numerous in plants, possibly reflecting the remarkable ability of plants to modulate their postembryonic development. Many plant cells also can continue DNA replication in the absence of mitosis, a process known as endoreduplication, causing polyploidy. Here, we review the molecular mechanisms that regulate cell division and endoreduplication and we discuss our understanding, albeit very limited, on how the cell cycle is integrated with plant development.
781 citations
TL;DR: Advances in the yeast retrograde signaling pathway are reviewed and its regulatory factors and regulatory mechanisms, its physiological functions, and its connection to nutrient sensing, TOR signaling, and aging are highlighted.
Abstract: Mitochondrial retrograde signaling is a pathway of communication from mitochondria to the nucleus under normal and pathophysiological conditions. The best understood of such pathways is retrograde signaling in the budding yeast Saccharomyces cerevisiae. It involves multiple factors that sense and transmit mitochondrial signals to effect changes in nuclear gene expression; these changes lead to a reconfiguration of metabolism to accommodate cells to defects in mitochondria. Analysis of regulatory factors has provided us with a mechanistic view of regulation of retrograde signaling. Here we review advances in the yeast retrograde signaling pathway and highlight its regulatory factors and regulatory mechanisms, its physiological functions, and its connection to nutrient sensing, TOR signaling, and aging.
616 citations
TL;DR: This review examines several well-established model systems for c-di-GMP signaling, including Pseudomonas, Vibrio, Caulobacter, and Salmonella, and on their role in transmitting environmental stimuli into a range of different cellular functions.
Abstract: Cyclic-di-GMP is a ubiquitous second messenger in bacteria. The recent discovery that c-di-GMP antagonistically controls motility and virulence of single, planktonic cells on one hand and cell adhesion and persistence of multicellular communities on the other has spurred interest in this regulatory compound. Cellular levels of c-di-GMP are controlled through the opposing activities of diguanylate cyclases and phosphodiesterases, which represent two large families of output domains found in bacterial one- and two-component systems. This review concentrates on structural and functional aspects of diguanylate cyclases and phosphodiesterases, and on their role in transmitting environmental stimuli into a range of different cellular functions. In addition, we examine several well-established model systems for c-di-GMP signaling, including Pseudomonas, Vibrio, Caulobacter, and Salmonella.
612 citations
TL;DR: Following DNA repair, the checkpoint pathway is inactivated in a process termed recovery, and a related but genetically distinct process, adaptation, controls cell cycle re-entry in the face of unrepairable damage.
Abstract: In response to even a single chromosomal double-strand DNA break, cells enact the DNA damage checkpoint. This checkpoint triggers cell cycle arrest, providing time for the cell to repair damaged chromosomes before entering mitosis. This mechanism helps prevent the segregation of damaged or mutated chromosomes and thus promotes genomic stability. Recent work has elucidated the molecular mechanisms underlying several critical steps in checkpoint activation, notably the recruitment of the upstream checkpoint kinases of the ATM and ATR families to different damaged DNA structures and the molecular events through which these kinases activate their effectors. Chromatin modification has emerged as one important component of checkpoint activation and maintenance. Following DNA repair, the checkpoint pathway is inactivated in a process termed recovery. A related but genetically distinct process, adaptation, controls cell cycle re-entry in the face of unrepairable damage.
567 citations
TL;DR: How bacterial pathogens exploit localized hypermutation, through polymerase slippage of simple sequence repeats (SSRs), to generate phenotypic variation and enhanced fitness is reviewed.
Abstract: Bacterial pathogens face stringent challenges to their survival because of the many unpredictable, often precipitate, and dynamic changes that occur in the host environment or in the process of transmission from one host to another. Bacterial adaptation to their hosts involves either a mechanism for sensing and responding to external changes or the selection of variants that arise through mutation. Here we review how bacterial pathogens exploit localized hypermutation, through polymerase slippage of simple sequence repeats (SSRs), to generate phenotypic variation and enhanced fitness. These SSRs are located within the reading frame or in the promoter of a subset of genes, often termed contingency loci, whose functions are usually involved in direct interactions with host structures.
409 citations
TL;DR: The potential connections between circadian oscillations in gene expression and circadian oscillation in metabolic activity are a major focus of this review.
Abstract: This review examines the connections between circadian and metabolic rhythms. Examples from a wide variety of well-studied organisms are used to illustrate some of the genetic and molecular pathways linking circadian timekeeping to metabolism. The principles underlying biological timekeeping by intrinsic circadian clocks are discussed briefly. Genetic and molecular studies have unambiguously identified the importance of gene expression feedback circuits to the generation of overt circadian rhythms. This is illustrated particularly well by the results of genome-wide expression studies, which have uncovered hundreds of clock-controlled genes in cyanobacteria, fungi, plants, and animals. The potential connections between circadian oscillations in gene expression and circadian oscillations in metabolic activity are a major focus of this review.
348 citations
TL;DR: The great majority of susceptibility loci remain to be identified and the advent of large-scale genome-wide association scans offers a new approach to defining many of these.
Abstract: Host genetic factors play a major role in determining differential susceptibility to major infectious diseases of humans, such as malaria, HIV/AIDS, tuberculosis, and invasive pneumococcal disease. Progress in identifying the relevant genetic loci has come from a variety of approaches. Most convincing associations have been identified by case-control studies assessing biologically plausible candidate genes. All six of the genes that have a major effect on infectious disease susceptibility in humans have been identified in this way. However, recently genome-wide linkage analysis of affected sibling pairs has identified susceptibility loci for chronic infections such as leprosy and chronic hepatitis B virus persistence. Other approaches used successfully have included assessment in humans of the homologues of susceptibility genes mapped and identified in murine models. However, the great majority of susceptibility loci remain to be identified and the advent of large-scale genome-wide association sca...
267 citations
TL;DR: Understanding the interactions between these three classes of tumor-suppressor genes will improve the understanding of how cell and tissue growth are coordinated during organismal development and perturbed in disease states such as cancer.
Abstract: Inactivating mutations in the Drosophila tumor-suppressor genes result in tissue overgrowth. This can occur because the mutant tissue either grows faster than wild-type tissue and/or continues to grow beyond a time when wild-type tissue stops growing. There are three general classes of tumor-suppressor genes that regulate the growth of imaginal disc epithelia. Mutations in the hyperplastic tumor-suppressor genes result in increased cell proliferation but do not disrupt normal tissue architecture. These genes include pten, Tsc1, Tsc2, and components of the hippo/salvador/warts pathway. Mutations in a second class of genes, the neoplastic tumor-suppressor genes, disrupt proteins that function either as scaffolds at cell-cell junctions (scribble, discs large, lgl) or as components of the endocytic pathway (avalanche, rab5, ESCRT components). For the third group, the nonautonomous tumor-suppressor genes, mutant cells stimulate the proliferation of adjacent wild-type cells. Understanding the interactions between these three classes of genes will improve our understanding of how cell and tissue growth are coordinated during organismal development and perturbed in disease states such as cancer.
236 citations
TL;DR: This work reviews recent data on cellular responses to DNA double-strand breaks and investigates whether a cell may arrest division via checkpoint activation to fix DSBs or commit suicide by apoptosis.
Abstract: DNA double-strand breaks (DSBs) produce a number of cellular responses, some mutually exclusive. Depending on where on the chromosome it occurs, a DSB may become preserved inside a telomere or eliminated by repair. A cell may arrest division via checkpoint activation to fix DSBs or commit suicide by apoptosis. What determines the outcome: to bury, fix, or succumb to DNA DSBs? With this question in mind, we review recent data on cellular responses to DSBs.
227 citations
TL;DR: A review of seminal and recent ideas about the origins of introns can be found in this article, where the authors discuss the origins and causes of intron evolution and propose the Intron-First (INF) theory.
Abstract: Research into the origins of introns is at a critical juncture in the resolution of theories on the evolution of early life (which came first, RNA or DNA?), the identity of LUCA (the last universal common ancestor, was it prokaryotic- or eukaryotic-like?), and the significance of noncoding nucleotide variation. One early notion was that introns would have evolved as a component of an efficient mechanism for the origin of genes. But alternative theories emerged as well. From the debate between the “introns-early” and “introns-late” theories came the proposal that introns arose before the origin of genetically encoded proteins and DNA, and the more recent “introns-first” theory, which postulates the presence of introns at that early evolutionary stage from a reconstruction of the “RNA world.” Here we review seminal and recent ideas about intron origins. Recent discoveries about the patterns and causes of intron evolution make this one of the most hotly debated and exciting topics in molecular evolut...
TL;DR: The 8-9-Mb Streptomyces chromosome is linear, with a "core" containing essential genes and "arms" carrying conditionally adaptive genes that can sustain large deletions in the laboratory.
Abstract: The 8-9-Mb Streptomyces chromosome is linear, with a "core" containing essential genes and "arms" carrying conditionally adaptive genes that can sustain large deletions in the laboratory. Bidirectional chromosome replication from a central oriC is completed by "end-patching," primed from terminal proteins covalently bound to the free 5'-ends. Plasmid-mediated conjugation involves movement of double-stranded DNA by proteins resembling other bacterial motor proteins, probably via hyphal tip fusion, mediated by these transfer proteins. Circular plasmids probably transfer chromosomes by transient integration, but linear plasmids may lead the donor chromosome end-first into the recipient by noncovalent association of ends. Transfer of complete chromosomes may be the rule. The recipient mycelium is colonized by intramycelial spreading of plasmid copies, under the control of plasmid-borne "spread" genes. Chromosome partition into prespore compartments of the aerial mycelium is controlled in part by actin- and tubulin-like proteins, resembling MreB and FtsZ of other bacteria.
TL;DR: This work will review and discuss the specific contribution of each of the two chemosensory systems that ensure specific behavioral responses to conspecific animals.
Abstract: Molecular approaches and genetic manipulations have provided novel insights into the processing of pheromone-mediated information by the olfactory and vomeronasal systems of mammals. We will review and discuss the specific contribution of each of the two chemosensory systems that ensure specific behavioral responses to conspecific animals.
TL;DR: Recent developments in understanding of the roles that helicases play in the intimately linked processes of replication fork repair and homologous recombination are reviewed and how the cell has evolved many distinct, and sometimes antagonistic, uses for these enzymes are highlighted.
Abstract: DNA helicases are found in all kingdoms of life and function in all DNA metabolic processes where the two strands of duplex DNA require to be separated. Here, we review recent developments in our understanding of the roles that helicases play in the intimately linked processes of replication fork repair and homologous recombination, and highlight how the cell has evolved many distinct, and sometimes antagonistic, uses for these enzymes.
TL;DR: The biochemical mechanism of NHEJ in double-strand break repair, and in the response to dysfunctional telomeres are reviewed, to highlight how the N HEJ machinery and the telomere complex are evolving to maintain genome stability.
Abstract: Double-strand breaks are a cataclysmic threat to genome integrity. In higher eukaryotes the predominant recourse is the nonhomologous end-joining (NHEJ) double-strand break repair pathway. NHEJ is a versatile mechanism employing the Ku heterodimer, ligase IV/XRCC4 and a host of other proteins that juxtapose two free DNA ends for ligation. A critical function of telomeres is their ability to distinguish the ends of linear chromosomes from double-strand breaks, and avoid NHEJ. Telomeres accomplish this feat by forming a unique higher order nucleoprotein structure. Paradoxically, key components of NHEJ associate with normal telomeres and are required for proper length regulation and end protection. Here we review the biochemical mechanism of NHEJ in double-strand break repair, and in the response to dysfunctional telomeres. We discuss the ways in which NHEJ proteins contribute to telomere biology, and highlight how the NHEJ machinery and the telomere complex are evolving to maintain genome stability.
TL;DR: Analysis of egg-laying-defective mutants has provided insight into a number of conserved processes in nervous system development, including neurogenesis, cell migration, and synaptic patterning, as well as aspects of excitable cell signal transduction and neuromodulation.
Abstract: Genetic studies of behavior in the nematode Caenorhabditis elegans have provided an effective approach to investigate the molecular and cellular basis of nervous system function and development. Among the best studied behaviors is egg-laying, the process by which hermaphrodites deposit developing embryos into the environment. Egg-laying involves a simple motor program involving a small network of motorneurons and specialized smooth muscle cells, which is regulated by a variety of sensory stimuli. Analysis of egg-laying–defective mutants has provided insight into a number of conserved processes in nervous system development, including neurogenesis, cell migration, and synaptic patterning, as well as aspects of excitable cell signal transduction and neuromodulation.
TL;DR: The Epidermal Growth Factor Receptor tyrosine kinase signaling pathway provides a prime vantage point from which to explore emerging principles in developmental signal transduction.
Abstract: One of the challenges of modern biology is to understand how cells within a developing organism generate, integrate, and respond to dynamic informational cues. Based on over two decades of intensive research, many parts and subroutines of the responsible signal transduction networks have been identified and functionally characterized. From this work, it has become evident that a complicated interplay between signaling pathways, involving extensive feedback regulation and multiple levels of cross-talk, underlies even the “simplest” developmental decision. Thus a signaling pathway can no longer be thought of as a rigid linear process, but rather must be considered a dynamic, self-interacting, and self-adjusting network. The Epidermal Growth Factor Receptor tyrosine kinase signaling pathway provides a prime vantage point from which to explore emerging principles in developmental signal transduction.
TL;DR: Finding the unexpected and being asked to demonstrate unequivocally the absence of a possible contaminant represent uncanny parallels between the discoveries that DNA encodes the genotype and that prions are infectious proteins.
Abstract: The resemblance between the discoveries that DNA is the basis of heredity and that prions are infectious proteins is remarkable. Though four decades separated these two discoveries, the biochemical methodologies and scientific philosophies that were employed are surprisingly similar. In both cases, bioassays available at the time that the projects were initiated proved to be inadequate to support purification studies. Improved bioassays allowed the transforming principle (TP) to be purified from pneumococci and prions from scrapie-infected hamster brains. Publications describing TP as composed of DNA prompted some scientists to contend that undetected proteins must contaminate TP enriched fractions. The simplicity of DNA was thought to prevent it from encoding genetic information. By the time prions were discovered, the genomes of all infectious pathogens including viruses, bacteria, fungi and parasites had been shown to be comprised of nucleic acids and so an antithetical refrain became widely ec...