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1.
Claudia P. Spampinato 《Cellular and molecular life sciences : CMLS》2017,74(9):1693-1709
The genome integrity of all organisms is constantly threatened by replication errors and DNA damage arising from endogenous and exogenous sources. Such base pair anomalies must be accurately repaired to prevent mutagenesis and/or lethality. Thus, it is not surprising that cells have evolved multiple and partially overlapping DNA repair pathways to correct specific types of DNA errors and lesions. Great progress in unraveling these repair mechanisms at the molecular level has been made by several talented researchers, among them Tomas Lindahl, Aziz Sancar, and Paul Modrich, all three Nobel laureates in Chemistry for 2015. Much of this knowledge comes from studies performed in bacteria, yeast, and mammals and has impacted research in plant systems. Two plant features should be mentioned. Plants differ from higher eukaryotes in that they lack a reserve germline and cannot avoid environmental stresses. Therefore, plants have evolved different strategies to sustain genome fidelity through generations and continuous exposure to genotoxic stresses. These strategies include the presence of unique or multiple paralogous genes with partially overlapping DNA repair activities. Yet, in spite (or because) of these differences, plants, especially Arabidopsis thaliana, can be used as a model organism for functional studies. Some advantages of this model system are worth mentioning: short life cycle, availability of both homozygous and heterozygous lines for many genes, plant transformation techniques, tissue culture methods and reporter systems for gene expression and function studies. Here, I provide a current understanding of DNA repair genes in plants, with a special focus on A. thaliana. It is expected that this review will be a valuable resource for future functional studies in the DNA repair field, both in plants and animals. 相似文献
2.
J. Hauschild-Quintern B. Petersen G. J. Cost H. Niemann 《Cellular and molecular life sciences : CMLS》2013,70(16):2969-2983
Zinc-finger nucleases (ZFNs) are engineered site-specific DNA cleavage enzymes that may be designed to recognize long target sites and thus cut DNA with high specificity. ZFNs mediate permanent and targeted genetic alteration via induction of a double-strand break at a specific genomic site. Compared to conventional homology-based gene targeting, ZFNs can increase the targeting rate by up to 100,000-fold; gene disruption via mutagenic DNA repair is similarly efficient. The utility of ZFNs has been shown in many organisms, including insects, amphibians, plants, nematodes, and several mammals, including humans. This broad range of tractable species renders ZFNs a useful tool for improving the understanding of complex physiological systems, to produce transgenic animals, cell lines, and plants, and to treat human disease. 相似文献
3.
The acquisition of an appropriate set of chemical modifications is required in order to establish correct structure of RNA molecules, and essential for their function. Modification of RNA bases affects RNA maturation, RNA processing, RNA quality control, and protein translation. Some RNA modifications are directly involved in the regulation of these processes. RNA epigenetics is emerging as a mechanism to achieve dynamic regulation of RNA function. Other modifications may prevent or be a signal for degradation. All types of RNA species are subject to processing or degradation, and numerous cellular mechanisms are involved. Unexpectedly, several studies during the last decade have established a connection between DNA and RNA surveillance mechanisms in eukaryotes. Several proteins that respond to DNA damage, either to process or to signal the presence of damaged DNA, have been shown to participate in RNA quality control, turnover or processing. Some enzymes that repair DNA damage may also process modified RNA substrates. In this review, we give an overview of the DNA repair proteins that function in RNA metabolism. We also discuss the roles of two base excision repair enzymes, SMUG1 and APE1, in RNA quality control. 相似文献
4.
U Hagen 《Experientia》1989,45(1):7-12
In order to analyze the mechanisms of biological radiation effects, the events after radiation energy absorption in irradiated organisms have to be studied by physico-chemical and biochemical methods. The radiation effects in vitro on biomolecules, especially DNA, are described, as well as their alterations in irradiated cells. Whereas in vitro, in aqueous solution, predominantly OH radicals are effective and lead to damage in single moieties of the DNA, in vivo the direct absorption of radiation energy leads to 'locally multiply-damaged sites', which produce DNA double-strand breaks and locally denatured regions. DNA damage will be repaired in irradiated cells. Error free repair leads to the original nucleotide sequence in the genome by excision or by recombination. "Error prone repair"(mutagenic repair), leads to mutation. However, the biochemistry of these processes, regulated by a number of genes, is poorly understood. In addition, more complex reactions, such as gene amplification and transposition of mobile gene elements, are responsible for mutation or malignant transformation. 相似文献
5.
Lavelle EC 《Cellular and molecular life sciences : CMLS》2005,62(23):2750-2770
Vaccination is a highly effective means of disease prevention and has saved countless lives worldwide over the past 200 years.
Traditional vaccines based on killed and attenuated organisms and inactivated toxins have constituted the majority of clinically
used vaccines to date, but novel vaccines based on subunits of these organisms will be increasingly represented in future.
In contrast to attenuated and whole cell vaccines, subunit vaccines do not generally contain immune-stimulatory components
and are poorly immunogenic. As a result, new, potent and safe adjuvants and delivery systems are needed to enhance the immunogenicity
of these vaccines. Furthermore, there is a drive to replace injected vaccines with those that can be administered by mucosal
routes. Since the induction of innate immunity is crucial for vaccines to elicit potent antigen specific immune responses,
a greater understanding of innate immunity at mucosal surfaces and the mechanism of action of adjuvants and delivery systems
is required.
Received 28 June 2005; received after revision 2 August 2005; accepted 30 August 2005 相似文献
6.
Double-strand breaks (DSBs) are the most detrimental form of DNA damage. Failure to repair these cytotoxic lesions can result
in genome rearrangements conducive to the development of many diseases, including cancer. The DNA damage response (DDR) ensures
the rapid detection and repair of DSBs in order to maintain genome integrity. Central to the DDR are the DNA damage checkpoints.
When activated by DNA damage, these sophisticated surveillance mechanisms induce transient cell cycle arrests, allowing sufficient
time for DNA repair. Since the term “checkpoint” was coined over 20 years ago, our understanding of the molecular mechanisms
governing the DNA damage checkpoint has advanced significantly. These pathways are highly conserved from yeast to humans.
Thus, significant findings in yeast may be extrapolated to vertebrates, greatly facilitating the molecular dissection of these
complex regulatory networks. This review focuses on the cellular response to DSBs in Saccharomyces cerevisiae, providing a comprehensive overview of how these signalling pathways function to orchestrate the cellular response to DNA
damage and preserve genome stability in eukaryotic cells. 相似文献
7.
Prochownik EV 《Cellular and molecular life sciences : CMLS》2005,62(21):2438-2459
The discovery of oncogenes (c-onc’s) and tumor suppressors (TS’s) has led to the concept that cancer arises from defects in
each of these classes of genes or their products. More recently, it has been appreciated that c-onc and TS proteins often
affect one another’s functions. Within this context, I review the two classical TS’s, p53 and the retinoblastoma protein,
and the consequences of their inactivation. The various forms of genomic instability (GI) that underly the high mutation rates
of transformed cells are then discussed. Particular emphasis is placed upon the concept that GI is not only an integral part
of the transformed state but is a prerequisite. Increased oxidative DNA damage, and/or an inabiliy to repair it, can lead
to GI. The review then discusses recent observations showing that loss of the TS protein peroxiredoxin 1 (prdx1) and increased
expression of the c-onc protein c-Myc, each leads to increased oxidative DNA damage. The critical nature of the c-onc-TS interaction
is underscored by that occurring between prdx1 and c-Myc, with the former protein regulating the production of DNA-damaging
reactive oxygen species by the latter. The intimate association between these proteins and others serves as a paradigm for
the exquisite balancing act that c-onc’s and TS’s must maintain in order to properly control normal DNA replication and cellular
proliferation while simultaneously minimizing the acquisition of potentially neoplastic mutations.
Received 10 May 2005; received after revision 3 July 2005; accepted 19 July 2005 相似文献
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Geminin is a multifunctional protein. After DNA replication is initiated during a cell cycle, geminin binds to Cdt1, one of the key DNA replication licensing factors. This highly regulated interaction sequestrates Cdt1, thus preventing DNA rereplication in the same cell cycle. In addition, geminin directly interacts with Six3 and Hox homeodomain proteins during embryogenesis and inhibits their functions. The regulation of Hox function by geminin also involves a transient association with the Hox repressive Polycomb complex. The functions of geminin to obstruct key molecules of both cell proliferation and embryonic development suggest a competitive coordination of these two processes.Received 10 December 2004; received after revision 27 January 2005; accepted March 2005 相似文献
12.
Chromosome integrity in response to chemically or radiation-induced chromosome breaks and the perturbation of ongoing replication
forks relies on multiple DNA repair mechanisms. However, repair of these lesions may lead to unwanted chromosome rearrangement
if not properly executed or regulated. As these types of chromosomal alterations threaten the cell’s and the organism’s very
own survival, multiple systems are developed to avoid or at least limit break-induced chromosomal rearrangements. In this
review, we highlight cellular strategies for repressing DNA break-induced chromosomal translocations in multiple model systems
including yeast, mouse, and human. These pathways select proper homologous templates or broken DNA ends for the faithful repair
of DNA breaks to avoid undesirable chromosomal translocations. 相似文献
13.
The search for the right partner: Homologous pairing and DNA strand exchange proteins in eukaryotes 总被引:13,自引:0,他引:13
W. -D. Heyer 《Cellular and molecular life sciences : CMLS》1994,50(3):223-233
Finding the right partner is a central problem in homologous recombination. Common to all models for general recombination is a homologous pairing and DNA strand exchange step. In prokaryotes this process has mainly been studied with the RecA protein ofEscherichia coli. Two approaches have been used to find homologous pairing and DNA strand exchange proteins in eukaryotes. A biochemical approach has resulted in numerous proteins from various organisms. Almost all of these proteins are biochemically fundamentally different from RecA. The in vivo role of these proteins is largely not understood. A molecular-genetical approach has identified structural homologs to theE. coli RecA protein in the yeastSaccharomyces cerevisiae and subsequently in other organisms including other fungi, mammals, birds, and plants. The biochemistry of the eukaryotic RecA homologs is largely unsolved. For the fungal RecA homologs (S. cerevisiae RAD51, RAD55, RAD57, DMC1; Schizosaccharomyces pombe rad51; Neurospora crassa mei3) a role in homologous recombination and recombinational repair is evident. Besides recombination, homologous pairing proteins might be involved in other cellular processes like chromosome pairing or gene inactivation. 相似文献
14.
Base excision DNA repair 总被引:2,自引:0,他引:2
Zharkov DO 《Cellular and molecular life sciences : CMLS》2008,65(10):1544-1565
DNA repair is a collection of several multienzyme, multistep processes keeping the cellular genome intact against genotoxic insults. One of these processes is base excision repair, which deals with the most ubiquitous lesions in DNA: oxidative base damage, alkylation, deamination, sites of base loss and single-strand breaks, etc. Individual enzymes acting in base excision repair have been identified. The recent years were marked with many advances in understanding of their structure and many interactions that make base excision repair a functional, versatile system. This review describes the current knowledge of structural biology and biochemistry of individual steps of base excision repair, several subpathways of the common base excision repair pathway, and interactions of the repair process with other cellular processes. 相似文献
15.
Transmission of the genetic information from the parental DNA strand to the offspring is crucial for the survival of any living species. In nature, all DNA synthesis in DNA replication, recombination and repair is catalyzed by DNA polymerases and depends on their ability to select the canonical nucleobase pair from a pool of structurally similar building blocks. Recently, a wealth of valuable new insights into DNA polymerase mechanisms have been gained through application of carefully designed synthetic nucleotides and oligonucleotides in functional enzyme studies. The applied analogues exhibit features that differ in certain aspects from their natural counterparts and, thus, allow investigation of the involvement and efficacy of a chosen particular aspect on the entire complex enzyme mechanism. This review will focus on a depiction of the efforts that have been undertaken towards the development of nucleotide analogues with carefully altered properties. The different approaches will be discussed in the context of the motivation and the problem under investigation.Received 16 March 2005; received after revision 5 May 2005; accepted 8 June 2005 相似文献
16.
Wikenheiser-Brokamp KA 《Cellular and molecular life sciences : CMLS》2006,63(7-8):767-780
The retinoblastoma (Rb) gene was identified as the first tumor suppressor gene two decades ago. Since this initial discovery,
it has become clear that deregulated Rb function constitutes a hallmark of human malignancies. Rb is a well-established regulator
of the cell cycle. Rb has also been implicated in playing a role in a wide variety of cellular processes including DNA repair,
cellular senescence, cell fate determination and apoptosis. Animals lacking Rb and/or its family members p107 and p130 have
led scientists to uncover new and exciting roles for this protein family in development as well as tumor suppression. The
ability to ablate Rb in a temporal and cell-type-specific manner has offered further, often unexpected, insights into Rb function.
This review summarizes the phenotypic consequences of Rb family ablation in mice, and discusses how these findings contribute
to the increasingly complex picture of Rb family function in development and tumor suppression.
Received 11 October 2005; received after revision 16 November 2005; accepted 28 November 2005 相似文献
17.
Psychrophilic organisms have successfully colonized polar and alpine regions and are able to grow efficiently at sub-zero
temperatures. At the enzymatic level, such organisms have to cope with the reduction of chemical reaction rates induced by
low temperatures in order to maintain adequate metabolic fluxes. Thermal compensation in cold-adapted enzymes is reached through
improved turnover number and catalytic efficiency. This optimization of the catalytic parameters can originate from a highly
flexible structure which provides enhanced abilities to undergo conformational changes during catalysis. Thermal instability
of cold-adapted enzymes is therefore regarded as a consequence of their conformational flexibility. A survey of the psychrophilic
enzymes studied so far reveals only minor alterations of the primary structure when compared to mesophilic or thermophilic
homologues. However, all known structural factors and weak interactions involved in protein stability are either reduced in
number or modified in order to increase their flexibility. 相似文献
18.
Transmembrane ion channels play a crucial role in the existence of all living organisms. They partition the exterior from
the interior of the cell, maintain the proper ionic gradient across the cell membrane and facilitate signaling between cells.
To perform these functions, ion channels must be highly selective, allowing some types of ions to pass while blocking the
passage of others. Here we review a number of studies that have helped to elucidate the mechanisms by which ion channels discriminate
between ions of differing charge, focusing on four channel families as examples: gramicidin, ClC chloride, voltage-gated calcium
and potassium channels. The recent availability of high-resolution structural data has meant that the specific inter-atomic
interactions responsible for valence selectivity can be pinpointed. Not surprisingly, electrostatic considerations have been
shown to play an important role in ion specificity, although many details of the origins of this discrimination remain to
be determined.
Received 4 September 2005; received after revision 17 October 2005; accepted 2 November 2005 相似文献
19.
Endonuclease V: an unusual enzyme for repair of DNA deamination 总被引:1,自引:1,他引:0
Weiguo Cao 《Cellular and molecular life sciences : CMLS》2013,70(17):3145-3156
Endonuclease V (endo V) was first discovered as the fifth endonuclease in Escherichia coli in 1977 and later rediscovered as a deoxyinosine 3′ endonuclease. Decades of biochemical and genetic investigations have accumulated rich information on its role as a DNA repair enzyme for the removal of deaminated bases. Structural and biochemical analyses have offered invaluable insights on its recognition capacity, catalytic mechanism, and multitude of enzymatic activities. The roles of endo V in genome maintenance have been validated in both prokaryotic and eukaryotic organisms. The ubiquitous nature of endo V in the three domains of life: Bacteria, Archaea, and Eukaryotes, indicates its existence in the early evolutionary stage of cellular life. The application of endo V in mutation detection and DNA manipulation underscores its value beyond cellular DNA repair. This review is intended to provide a comprehensive account of the historic aspects, biochemical, structural biological, genetic and biotechnological studies of this unusual DNA repair enzyme. 相似文献
20.
Cabelof DC 《Cellular and molecular life sciences : CMLS》2012,69(5):727-740
Mouse models of DNA repair deficiency are useful tools for determining susceptibility to disease. Cancer predisposition and
premature aging are commonly impacted by deficiencies in DNA repair, presumably as a function of reduced genomic fitness.
In this review, a comprehensive analysis of all DNA repair mutant mouse models has been completed in order to assess the importance
of haploinsufficiency for these genes. This analysis brings to light a clear role for haploinsufficiency in disease predisposition.
Unfortunately, much of the data on heterozygous models are buried or underinvestigated. In light of a better understanding
that the role of DNA repair haploinsufficiency may play in penetrance of other oncogenic or disease causing factors, it may
be in the interest of human health and disease prevention to further investigate the phenotypes in many of these mouse models. 相似文献