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1.
Kirkpatrick DT 《Cellular and molecular life sciences : CMLS》1999,55(3):437-449
Numerous proteins are involved in the nucleotide excision repair (NER) and DNA mismatch repair (MMR) pathways. The function
and specificity of these proteins during the mitotic cell cycle has been actively investigated, in large part due to the involvement
of these systems in human diseases. In contrast, comparatively little is known about their functioning during meiosis. At
least three repair pathways operate during meiosis in the yeast Saccharomyces cerevisiae to repair mismatches that occur as a consequence of heteroduplex formation in recombination. The first pathway is similar
to the one acting during postreplicative mismatch repair in mitotically dividing cells, while two pathways are responsible
for the repair of large loops during meiosis, using proteins from MMR and NER systems. Some MMR proteins also help prevent
recombination between diverged sequences during meiosis, and act late in recombination to affect the resolution of crossovers.
This review will discuss the current status of DNA mismatch repair and nucleotide excision repair proteins during meiosis,
especially in the yeast S. cerevisiae.
Received 21 September 1998; received after revision 23 November 1998; accepted 23 November 1998 相似文献
2.
The anti-metabolite 5-fluorouracil (5-FU) is employed clinically to manage solid tumors including colorectal and breast cancer.
Intracellular metabolites of 5-FU can exert cytotoxic effects via inhibition of thymidylate synthetase, or through incorporation
into RNA and DNA, events that ultimately activate apoptosis. In this review, we cover the current data implicating DNA repair
processes in cellular responsiveness to 5-FU treatment. Evidence points to roles for base excision repair (BER) and mismatch
repair (MMR). However, mechanistic details remain unexplained, and other pathways have not been exhaustively interrogated.
Homologous recombination is of particular interest, because it resolves unrepaired DNA intermediates not properly dealt with
by BER or MMR. Furthermore, crosstalk among DNA repair pathways and S-phase checkpoint signaling has not been examined. Ongoing
efforts aim to design approaches and reagents that (i) approximate repair capacity and (ii) mediate strategic regulation of
DNA repair in order to improve the efficacy of current anticancer treatments.
Received 08 September 2008; received after revision 25 September 2008; accepted 03 October 2008 相似文献
3.
Human MutY: gene structure,protein functions and interactions,and role in carcinogenesis 总被引:7,自引:0,他引:7
Faithful maintenance of the genome is crucial to the individual and the species. Oxidative DNA damage, such as 8-oxo-7,8-dihydroguanine (8-oxoG), poses a major threat to genomic integrity. 8-OxoG can mispair with 2-deoxycytidine 5-triphosphate or with 2-deoxyadenosine triphosphate during DNA replication, forming C8-oxoG and A8-oxoG mispairs. Human MutY is responsible for recognition and removal of the inappropriately inserted adenine in an A8-oxoG mispair. If unrepaired, the A8-oxoG mispairs can result in deleterious C:G to A:T transversions. Human MutY functions in a postreplication repair pathway and is targeted to the newly synthesized daughter strand of DNA for removal of the adenine base. The human MutY protein is targeted to both the mitochondria and the nucleus and associates with the proliferating cell nuclear antigen, apurinic/ apyrimidinic endonuclease 1, replication protein A and mutS homolog 6 proteins. Mutations in the human MutY gene and defective activity of the human MutY protein have been detected in cancer. A direct correlation between defective A8-oxoG repair and increased levels of genomic 8-oxoG has now been established.Received 10 February 2003; received after revision 7 April 2003; accepted 14 April 2003 相似文献
4.
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
5.
Some features of base pair mismatch repair and its role in the formation of genetic recombinants 总被引:2,自引:0,他引:2
M. S. Fox J. P. Radicella K. Yamamoto 《Cellular and molecular life sciences : CMLS》1994,50(3):253-260
For the formation of recombinants involving closely linked markers, two distinct processes play a role. The recombinational interaction between homologous DNA molecules results in the presence of heteroduplex DNA joining the parental components of the recombinant. The presence of markers distinguishing the parents in the region of heteroduplex DNA can result in base pair mismatches. The post recombination repair of such mismatches can contribute to the separation of closely linked markers. The processes responsible for such repair also play roles in mutation avoidance. The specificities, functions and contribution to the formation of recombinants for closely linked markers of the processes inEscherichia coli are described. 相似文献
6.
Biochemical aspects of radiation biology 总被引:1,自引:0,他引:1
U. Hagen 《Cellular and molecular life sciences : CMLS》1989,45(1):7-12
Summary 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
7.
Sokolowska M Kaus-Drobek M Czapinska H Tamulaitis G Siksnys V Bochtler M 《Cellular and molecular life sciences : CMLS》2007,64(18):2351-2357
It has long been known that most Type II restriction endonucleases share a conserved core fold and similar active-sites. The
same core folding motif is also present in the MutH protein, a component of the bacterial DNA mismatch repair machinery. In
contrast to most Type II restriction endonucleases, which assemble into functional dimers and catalyze double-strand breaks,
MutH is a monomer and nicks hemimethylated DNA. Recent biochemical and crystallographic studies demonstrate that the restriction
enzymes BcnI and MvaI share many additional features with MutH-like proteins, but not with most other restriction endonucleases.
The structurally similar monomers all recognize approximately symmetric target sequences asymmetrically. Differential sensitivities
to slight substrate asymmetries, which could be altered by protein engineering, determine whether the enzymes catalyze only
single-strand nicks or double-strand breaks.
M. Sokolowska, M. Kaus-Drobek: These authors contributed equally to this work.
Received 12 March 2007; received after revision 28 April 2007; accepted 3 May 2007 相似文献
8.
Telomeres were first recognized as a bona fide constituent of the chromosome based on their inability to rejoin with broken chromosome ends produced by radiation. Today,
we recognize two essential and interrelated properties of telomeres. They circumvent the so-called end-replication problem
faced by genomes composed of linear chromosomes, which erode from their termini with each successive cell division. Equally
vital is the end-capping function that telomeres provide, which is necessary to deter chromosome ends from illicit recombination.
This latter property is critical in facilitating the distinction between the naturally occurring DNA double-strand breaks
(DSBs) found at chromosome ends (i.e., telomeres) and DSBs produced by exogenous agents. Here we discuss, in a brief historical narrative, key discoveries that
led investigators to appreciate the unique properties of telomeres in protecting chromosome ends, and the consequences of
telomere dysfunction, particularly as related to recombination involving radiation-induced DSBs.
Dedication. In appreciation of his heart-felt commitment to research and education, and the life-long influence he has had on the lives
of students and colleagues, the authors wish to dedicate this paper to Professor Joel S. Bedford.
Received 21 May 2007; received after revision 28 June 2007; accepted 6 August 2007 相似文献
9.
Mosesso P Piane M Palitti F Pepe G Penna S Chessa L 《Cellular and molecular life sciences : CMLS》2005,62(4):485-491
The cells of an ataxia-oculomotor apraxia type 1 (AOA1) patient, homozygous for a new aprataxin mutation (T739C), were treated with camptothecin, an inhibitor of DNA topoisomerase I which induces DNA single-strand breaks. DNA damage was evaluated by cytogenetic analysis of chromosomal aberrations. The results obtained showed marked and dose-related increases in induced chromosomal aberrations in the patient and her heterozygous mother compared to the intrafamilial wild-type control. The alkaline comet assay confirmed this pattern. Moreover, the AOA1 cells did not show hypersensitivity to ionizing radiation, i.e. X-rays. These findings clearly indicate the direct involvement of aprataxin in the DNA single-strand-break repair machinery.Received 6 October 2004; received after revision 24 November 2004; accepted 28 December 2004P. Mosesso and M. Piane contributed equally to this work. 相似文献
10.
Recent work has led to significant advances in our understanding of the late steps of genetic recombination and the post-replicational repair of DNA. The RuvA and RuvB proteins have been shown to interact with recombination intermediates and catalyse the branch migration of Holliday junctions. Although both proteins are required for branch migration, each plays a defined role with RuvA acting as a specificity factor that directs RuvB (an ATPase) to the junction. The RuvB ATPase provides the motor for branch migration. The next step is catalysed by RuvC protein which recognises Holliday junctions and promotes their resolution by endonucleolytic cleavage. New data indicates an alternative pathway for Holliday junction processing. This pathway involves RecG, a branch migration protein which is functionally analogous to RuvAB, and a protein (activated by arus mutation) which works with RecG to process intermediates independently of RuvA, RuvB and RuvC. 相似文献
11.
H. D. Lohrer 《Cellular and molecular life sciences : CMLS》1996,52(4):316-328
A proportion of the population is exposed to acute doses of ionizing radiation through medical treatment or occupational accidents, with little knowledge of the immedate effects. At the cellular level, ionizing radiation leads to the activation of a genetic program which enables the cell to increase its chances of survival and to minimize detrimental manifestations of radiation damage. Cytotoxic stress due to ionizing radiation causes genetic instability, alterations in the cell cycle, apoptosis, or necrosis. Alterations in the G1, S and G2 phases of the cell cycle coincide with improved survival and genome stability. The main cellular factors which are activated by DNA damage and interfere with the cell cycle controls are: p53, delaying the transition through the G1-S boundary; p21WAF1/CIPI, preventing the entrance into S-phase; proliferating cell nuclear antigen (PCNA) and replication protein A (RPA), blocking DNA replication; and the p53 variant protein p53as together with the retinoblastoma protein (Rb), with less defined functions during the G2 phase of the cell cycle. By comparing a variety of radioresistant cell lines derived from radiosensitive ataxia talangiectasia cells with the parental cells, some essential mechanisms that allow cells to gain radioresistance have been identified. The results so far emphasise the importance of an adequate delay in the transition from G2 to M and the inhibition of DNA replication in the regulation of the cell cycle after exposure to ionizing radiation. 相似文献
12.
Le Bouffant R Cormier P Cueff A Bellé R Mulner-Lorillon O 《Cellular and molecular life sciences : CMLS》2007,64(13):1723-1734
DNA integrity checkpoint control was studied in the sea urchin early embryo. Treatment of the embryos with genotoxic agents
such as methyl methanesulfonate (MMS) or bleomycin induced the activation of a cell cycle checkpoint as evidenced by the occurrence
of a delay or an arrest in the division of the embryos and an inhibition of CDK1/cyclin B activating dephosphorylation. The
genotoxic treatment was shown to induce DNA damage that depended on the genotoxic concentration and was correlated with the
observed cell cycle delay. At low genotoxic concentrations, embryos were able to repair the DNA damage and recover from checkpoint
arrest, whereas at high doses they underwent morphological and biochemical changes characteristic of apoptosis. Finally, extracts
prepared from embryos were found to be capable of supporting DNA repair in vitro upon incubation with oligonucleotides mimicking damage. Taken together, our results demonstrate that sea urchin early embryos
contain fully functional and activatable DNA damage checkpoints. Sea urchin embryos are discussed as a promising model to
study the signaling pathways of cell cycle checkpoint, DNA repair and apoptosis, which upon deregulation play a significant
role in the origin of cancer.
Received 10 April 2007; accepted 23 April 2007 相似文献
13.
A. Shukla P. Chaurasia S. R. Bhaumik 《Cellular and molecular life sciences : CMLS》2009,66(8):1419-1433
Methylation of lysine residues of histones is associated with functionally distinct regions of chromatin, and, therefore,
is an important epigenetic mark. Over the past few years, several enzymes that catalyze this covalent modification on different
lysine residues of histones have been discovered. Intriguingly, histone lysine methylation has also been shown to be cross-regulated
by histone ubiquitination or the enzymes that catalyze this modification. These covalent modifications and their cross-talks
play important roles in regulation of gene expression, heterochromatin formation, genome stability, and cancer. Thus, there
has been a very rapid progress within past several years towards elucidating the molecular basis of histone lysine methylation
and ubiquitination, and their aberrations in human diseases. Here, we discuss these covalent modifications with their cross-regulation
and roles in controlling gene expression and stability.
Received 24 September 2008; received after revision 21 November 2008; accepted 28 November 2008 相似文献
14.
Homologous recombination in fission yeast: Absence of crossover interference and synaptonemal complex 总被引:8,自引:0,他引:8
The study of homologous recombination in the fission yeastSchizosaccharomyces pombe has recently been extended to the cytological analysis of meiotic prophase. Unlike in most eukaryotes no tripartite SC structure is detectable, but linear elements resembling axial cores of other eukaryotes are retained. They may be indispensable for meiotic recombination and proper chromosome segregation in meiosis I. In addition fission yeast shows interesting features of chromosome organization in vegetative and meiotic cells: Centromeres and telomeres cluster and associate with the spindle pole body. The special properties of fission yeast meiosis correlate with the absence of crossover interference in meiotic recombination. These findings are discussed. In addition homologous recombination in fission yeast is reviewed briefly.This article is dedicated to Urs Leupold, the founder of fission yeast genetics. 相似文献
15.
D. G. MacPhee 《Cellular and molecular life sciences : CMLS》1996,52(4):357-363
This paper describes a mechanism which permits somatic cells to generate random mutations in the complete absence of cell proliferation. Knowledge of the existence of this mechanism should provide us with the basis for a better understanding of a number of important biological phenomena, and in particular may help to explain the origins of many human cancers. 相似文献
16.
The correct repair of double-strand breaks (DSBs) is essential for the genomic integrity of a cell, as inappropriate repair
can lead to chromosomal rearrangements such as translocations. In many hematologic cancers and sarcomas, translocations are
the etiological factor in tumorigenesis, resulting in either the deregulation of a proto-oncogene or the expression of a fusion
protein with transforming properties. Mammalian cells are able to repair DSBs by pathways involving homologous recombination
and nonhomologous end-joining. The analysis of translocation breakpoints in a number of cancers and the development of model
translocation systems are beginning to shed light on specific DSB repair pathway(s) responsible for the improper repair of
broken chromosomes.
Received 19 June 2001; received after revision 6 September 2001; accepted 11 September 2001 相似文献
17.
T. M. Koval 《Cellular and molecular life sciences : CMLS》1987,43(4):445-446
Summary Cell survival and photoreactivation of 254 nm ultraviolet (UV) light damage in a wild typeDrosophila cell line was assayed by colony formation in liquid medium. Fo, Fq, and extrapolation number for the exponential portion of survival curves are 21 J/m2, 3.6 J/m2, and 1.5 for non-photoreactivated cells and 110 J/m2, 11.2 J/m2, and 1.3 for those exposed to photoreactivating light. Maximal photoreactivation occurs at the 100 J/m2 region of the curve. At 10 and 50% survival, 75–80% of the UV damage was photoreactivable. 相似文献
18.
In this article we review our current knowledge of the mechanisms by which point mutations arise in the mitochondrial DNA (mtDNA) of Saccharomyces cerevisiae and discuss to what extent these mechanisms operate in human mtDNA mutagenesis. The 3–5 exonuclease proofreading activity of Pol ensures accuracy of mtDNA replication in both yeast and humans, while the role of base excision repair in mtDNA error avoidance remains debated. The mitochondrial mismatch repair Msh1 protein, which removes transitions in yeast, is absent in humans, a particularity that might cause accumulation of transitions, while the most frequent substitution in yeast mtDNA is A:T to T:A transversion. Proofreading-deficient mutator human cell lines and knockin mice have been created. They will be useful for studying the mechanisms by which mtDNA mutations accumulate in diseases, ageing, malignancy and drug therapy.Received 25 May 2004; received after revision 21 June 2004; accepted 7 July 2004 相似文献
19.
Polarity of meiotic gene conversion in fungi: Contrasting views 总被引:9,自引:0,他引:9
The frequency of meiotic gene conversion often varies linearly from one end of the gene to the other. This phenomenon has been called polarity. In this review, we will primarily discuss studies of polarity that have been done in the yeastSaccharomyces cerevisiae (ARG4 and HIS4 loci) and inAscobolus (b2 locus) with an emphasis on possible mechanisms. The genetic and physical data obtained at these hotspots of recombination strongly suggests that the formation of a polarity gradient reflects both the frequency of heteroduplex formation and the processing of this recombination intermediate by mismatch-repair-dependent processes.This article is dedicated to the memory of Seymour Fogel. 相似文献
20.
Exposure to estrogens is a risk factor for breast and other human cancers. Initiation of breast, prostate and other cancers
has been hypothesized to result from reaction of specific estrogen metabolites, catechol estrogen-3,4-quinones, with DNA to
form depurinating adducts at the N-7 of guanine and N-3 of adenine by 1,4-Michael addition. The catechol of the carcinogenic
synthetic estrogen hexestrol, a hydrogenated derivative of diethylstilbestrol, is metabolized to its quinone, which reacts
with DNA to form depurinating adducts at the N-7 of guanine and N-3 of adenine. The catecholamine dopamine and the metabolite
catechol (1,2-dihydroxybenzene) of the leukemogen benzene can also be oxidized to their quinones, which react with DNA to
form predominantly analogous depurinating adducts. Apurinic sites formed by depurinating adducts are converted into tumor-initiating
mutations by error-prone repair. These mutations could initiate cancer by estrogens and benzene, and Parkinson's disease by
the neurotransmitter dopamine. These data suggest a unifying molecular mechanism of initiation for many cancers and neurodegenerative
diseases and lay the groundwork for designing strategies to assess risk and prevent these diseases.
Received 4 September 2001; received after revision 28 November 2001; accepted 2 December 2001 相似文献