Carotenoids and genomic stability

Epidemiological evidence abounds for a link between intake of carotenoids from fruit and vegetable foods and relatively low incidence of various cancers. However, intervention trials have shown, in some cases, a significant increase in occurrence of lung cancer in those volunteers taking supplements of beta-carotene. More information is clearly needed about the mechanism of action of carotenoids. Effects of carotenoids on cells in culture include inhibition of DNA synthesis and proliferation, changes in gene expression, decreased micronucleus frequency, and inhibition of transformation via synthesis of gap-junction proteins. Experiments with animal models are unsatisfactory because of the very poor uptake of carotenoids in rodents compared with man. In humans, oxidative damage to lymphocytes correlates negatively with plasma carotenoid concentrations, and the level of DNA damage is susceptible to reduction by carotenoid-rich foods. It seems clear that the carotenoids act as antioxidants in vivo, and yet this activity may not result in cancer prevention.     

Chromosome segregation and genomic stability

The acquisition of genomic instability is a crucial step in the development of human cancer. Genomic instability has multiple causes of which chromosomal instability (CIN) and microsatellite instability (MIN) have received the most attention. Whereas the connection between a MIN phenotype and cancer is now proven, the argument that CIN causes cancer remains circumstantial. Nonetheless, the ubiquity of aneuploidy in human cancers, particularly solid tumors, suggests a fundamental link between errors in chromosome segregation and tumorigenesis. Current research in the field is focused on elucidating the molecular basis of CIN, including the possible roles of defects in the spindle checkpoint and other regulators of mitosis.     

HSP70 and genomic stability

The 70 kDa heat shock proteins (HSP70s) were initially identified by their elevated expression following hyperthermic cell stress, however, these highly conserved proteins also protect critical cellular functions from a wider range of important environmental and physiological stresses. At least one result of HSP70 expression is inhibition of stress induced caspase activation as well as downstream events in the apoptotic cell death pathway. HSP70 have been reported upregulated in tumor cells, selective inhibition of such proteins might be valuable approach to treat cancer. A recent study revealed that cells with inactivated HSP70 displayed telomere instability and high frequency of spontaneous chromosomal aberrations, indicating a possible role for HSP70 proteins in the maintenance of genomic stability.     

Vitamin C and genomic stability

Vitamin C, a water-soluble glucose derivative, has considerable antioxidant activity in vitro, in part because of its ease of oxidation and because the semidehydroascorbate radical derived from it is of low reactivity. Vitamin C in vivo is an essential cofactor for a range of enzymes involved in diverse metabolic pathways, but much recent literature has focused on its antioxidant effects. Consumption of foods rich in Vitamin C (fruits and vegetables) is associated with decreased risk of cardiovascular disease, of many types of cancer and possibly of neurodegenerative disease, but the extent to which Vitamin C contributes to these effects is uncertain. Data using biomarkers of oxidative damage to DNA bases have given no compelling evidence to date that ascorbate supplements can decrease the levels of oxidative DNA damage in vivo, except perhaps in subjects with very low Vitamin C intakes. Similarly, there is no conclusive evidence from studies of strand breaks, micronuclei, or chromosomal aberrations for a protective effect of Vitamin C. There is limited evidence that supplements of Vitamin C might have beneficial effects in disorders of vascular function, and that diet-derived Vitamin C may decrease gastric cancer incidence in certain populations, but it is not clear whether it is the antioxidant or other properties of ascorbate that are responsible for these two actions.     

Alternative splicing and genomic stability

Alternative splicing allows an organism to make different proteins in different cells at different times, all from the same gene. In a cell that uses alternative splicing, the total length of all the exons is much shorter than in a cell that encodes the same set of proteins without alternative splicing. This economical use of exons makes genes more stable during reproduction and development because a genome with a shorter exon length is more resistant to harmful mutations. Genomic stability may be the reason why higher vertebrates splice alternatively. For a broad class of alternatively spliced genes, a formula is given for the increase in their stability.     

Caloric restriction and genomic stability

Caloric restriction (CR) reduces the incidence and progression of spontaneous and induced tumors in laboratory rodents while increasing mean and maximum life spans. It has been suggested that CR extends longevity and reduces age-related pathologies by reducing the levels of DNA damage and mutations that accumulate with age. This hypothesis is attractive because the integrity of the genome is essential to a cell/organism and because it is supported by observations that both cancer and immunological defects, which increase significantly with age and are delayed by CR, are associated with changes in DNA damage and/or DNA repair. Over the last three decades, numerous laboratories have examined the effects of CR on the integrity of the genome and the ability of cells to repair DNA. The majority of studies performed indicate that the age-related increase in oxidative damage to DNA is significantly reduced by CR. Early studies suggest that CR reduces DNA damage by enhancing DNA repair. With the advent of genomic technology and our increased understanding of specific repair pathways, CR has been shown to have a significant effect on major DNA repair pathways, such as NER, BER and double-strand break repair.     

Copper and genomic stability in mammals

As the free ion and in the form of some complexes, there is no doubt that copper can promote damage to cellular molecules and structures through radical formation. At the same time, and perhaps as a consequence, mammals have evolved means of minimizing levels of free copper ions and destructive copper complexes that enter the organism and its cells. These means include tight binding of copper ions to protein carriers and transporters; direct exchange of copper between protein carriers, transporters, and cuproenzymes; and mobilization of secretory mechanisms and excretory pathways, as needed. As a consequence, normally, and except under certain genetic conditions, copper is likely to be benign to most mammals and not responsible for genomic instability, including fragmentation of and/or alterations to DNA, induction of mutations or apoptosis, or other toxic events. Indeed, cuproenzymes are important members of the antioxidant system of the organism.     

Linking lncRNA to genomic stability

正Long Non-coding RNAs(lnc RNAs),usually derived from intergenic regions or introns,play distinct and important roles in diverse biological processes.Up to now,many types of non-coding RNAs have been identified across spe-     

Niacin requirements for genomic stability

Through its involvement in over 400 NAD(P)-dependent reactions, niacin status has the potential to influence every area of metabolism. Niacin deficiency has been linked to genomic instability largely through impaired function of the poly ADP-ribose polymerase (PARP) family of enzymes. In various models, niacin deficiency has been found to cause impaired cell cycle arrest and apoptosis, delayed DNA excision repair, accumulation of single and double strand breaks, chromosomal breakage, telomere erosion and cancer development. Rat models suggest that most aspects of genomic instability are minimized by the recommended levels of niacin found in AIN-93 formulations; however, some beneficial responses do occur in the range from adequate up to pharmacological niacin intakes. Mouse models show a wide range of protection against UV-induced skin cancer well into pharmacological levels of niacin intake. It is currently a challenge to compare animal and human data to estimate the role of niacin status in the risk of genomic instability in human populations. It seems fairly certain that some portion of even affluent populations will benefit from niacin supplementation, and some subpopulations are likely well below an optimal intake of this vitamin. With exposure to stressors, like chemotherapy or excess sunlight, suraphysiological doses of niacin may be beneficial.     

Role of magnesium in genomic stability

In cellular systems, magnesium is the second most abundant element and is involved in basically all metabolic pathways. At physiologically relevant concentrations, magnesium itself is not genotoxic, but is highly required to maintain genomic stability. Besides its stabilizing effect on DNA and chromatin structure, magnesium is an essential cofactor in almost all enzymatic systems involved in DNA processing. Most obvious in studies on DNA replication, its function is not only charge-related, but very specific with respect to the high fidelity of DNA synthesis. Furthermore, as essential cofactor in nucleotide excision repair, base excision repair and mismatch repair magnesium is required for the removal of DNA damage generated by environmental mutagens, endogenous processes, and DNA replication. Intracellular magnesium concentrations are highly regulated and magnesium acts as an intracellular regulator of cell cycle control and apoptosis. As evident from animal experiments and epidemiological studies, magnesium deficiency may decrease membrane integrity and membrane function and increase the susceptibility to oxidative stress, cardiovascular heart diseases as well as accelerated aging. The relationship to tumor formation is more complex; magnesium appears to be protective at early stages but promotes the growth of existing tumors. With respect to the magnesium status in humans, the daily intake in most industrialized countries does not reach the current recommended daily dietary allowances (RDA) values, and thus marginal magnesium deficiencies are very common.     

DNA damage-dependent cell cycle checkpoints and genomic stability

In response to genotoxic stress, which can be caused by environmental or endogenous genotoxic insults such as ionizing or ultraviolet radiation, various chemicals and reactive cellular metabolites, cell cycle checkpoints which slow down or arrest cell cycle progression can be activated, allowing the cell to repair or prevent the transmission of damaged or incompletely replicated chromosomes. Checkpoint machineries can also initiate pathways leading to apoptosis and the removal of a damaged cell from a tissue. The balance between cell cycle arrest and damage repair on one hand and the initiation of cell death, on the other hand, could determine if cellular or DNA damage is compatible with cell survival or requires cell elimination by apoptosis. Defects in these processes may lead to hypersensitivity to cellular stress, and susceptibility to DNA damage, genomic defects, and resistance to apoptosis, which characterize cancer cells. In this article, we have noted recent studies of DNA damage-dependent cell cycle checkpoints, which may be significant in preventing genomic instability.     

Poly(ADP-ribosylation) and genomic stability.

Poly(ADP-ribose) polymerases (PARPs) catalyze the synthesis of ADP-ribose polymers and attach them to specific target proteins. To date, 6 members of this protein family in humans have been characterized. The best-known PARP, PARP-1, is located within the nucleus and has a major function in DNA repair but also in the execution of cell death pathways. Other PARP enzymes appear to carry out highly specific functions. Most prominently, the tankyrases modify telomere-binding proteins and thereby regulate telomere maintenance. Since only a single enzyme, poly(ADP-ribose) glycohydrolase (PARG), has been identified, which degrades poly(ADP-ribose), it is expected that this protein has important roles in PARP-mediated regulatory processes. This review summarizes recent observations indicating that poly(ADP-ribosylation) represents a major mechanism to regulate genomic stability both when DNA is damaged by exogenous agents and during cell division.     

Vitamins/minerals and genomic stability in humans

Recommended dietary allowances (RDAs) of micronutrients have been traditionally derived as those levels necessary to prevent symptoms of deficiency diseases. There is increasing evidence that higher levels of many such micronutrients may be necessary for various DNA maintenance reactions, and that the current RDAs for some micronutrients may be inadequate to protect against genomic instability. Supplementation of a normal diet, with either vitamins and/or minerals or with isolated plant polyphenols, is becoming increasingly common in most Western populations. However, there is no clear agreement as to how much supplementation should occur, if at all, and genotypic differences are not accounted for. The 14 mini-reviews in this special issue summarise the role of specific micronutrients in various aspects of DNA maintenance: DNA synthesis, DNA repair, DNA methylation, gene mutation, chromosome breakage, chromosome segregation, gene expression, oxidative stress, necrosis and apoptosis. Evidence has been collated from mammalian and human experiments, both using in vitro cultures and in vivo approaches. Authors were asked to critically assess the strength of evidence as to whether the micronutrient can affect genomic stability in humans at realistic intake levels, and to estimate optimal dietary ranges where possible. Information on further research necessary is also documented. These reviews are an essential step towards a definition of RDAs designed to maintain genomic stability.     

Role of plant polyphenols in genomic stability

Polyphenols are a large and diverse class of compounds, many of which occur naturally in a range of food plants. The flavonoids are the largest and best-studied group of these. A range of plant polyphenols are either being actively developed or currently sold as dietary supplements and/or herbal remedies. Although, these compounds play no known role in nutrition (non-nutrients), many of them have properties including antioxidant, anti-mutagenic, anti-oestrogenic, anti-carcinogenic and anti-inflammatory effects that might potentially be beneficial in preventing disease and protecting the stability of the genome. However not all polyphenols and not all actions of individual polyphenols are necessarily beneficial. Some have mutagenic and/or pro-oxidant effects, as well as interfering with essential biochemical pathways including topoisomerase enzyme activities, prostanoid biosynthesis and signal transduction. There is a very large amount of in vitro data available, but far fewer animal studies, and these are not necessarily predictive of human effects because of differences in bacterial and hepatic metabolism of polyphenols between species. Epidemiological studies suggest that high green tea consumption in the Japanese population and moderate red wine consumption in the French population may be beneficial for heart disease and cancer, and these effects may relate to specific polyphenols. A small number of adequately controlled human intervention studies suggest that some, but not all polyphenol extracts or high polyphenol diets may lead to transitory changes in the antioxidative capacity of plasma in humans. However, none of these studies have adequately considered long-term effects on DNA or the chromosome and unequivocally associated these with polyphenol uptake. Furthermore, clinical trials have required intravenously administered polyphenols at concentrations around 1400mg/m(2) before effects are seen. These plasma concentrations are unlikely to be achieved using the dietary supplements currently available. More focused human studies are necessary before recommending specific polyphenolic supplements at specific doses in the human population.     

Selenium and its' role in the maintenance of genomic stability

Selenium (Se) is an essential micronutrient for humans, acting as a component of the unusual amino acids, selenocysteine (Se-Cys) and selenomethionine (Se-Met). Where Se levels are low, the cell cannot synthesise selenoproteins, although some selenoproteins and some tissues are prioritised over others. Characterised functions of known selenoproteins, include selenium transport (selenoprotein P), antioxidant/redox properties (glutathione peroxidases (GPxs), thioredoxin reductases and selenoprotein P) and anti-inflammatory properties (selenoprotein S and GPx4). Various forms of Se are consumed as part of a normal diet, or as a dietary supplement. Supplementation of tissue culture media, animal or human diets with moderate levels of certain Se compounds may protect against the formation of DNA adducts, DNA or chromosome breakage, and chromosome gain or loss. Protective effects have also been shown on mitochondrial DNA, and on telomere length and function. Some of the effects of Se compounds on gene expression may relate to modulation of DNA methylation or inhibition of histone deacetylation. Despite a large number of positive effects of selenium and selenoproteins in various model systems, there have now been some human clinical trials that have shown adverse effects of Se supplementation, according to various endpoints. Too much Se is as harmful as too little, with animal models showing a "U"-shaped efficacy curve. Current recommended daily allowances differ among countries, but are generally based on the amount of Se necessary to saturate GPx enzymes. However, increasing evidence suggests that other enzymes may be more important than GPx for Se action, that optimal levels may depend upon the form of Se being ingested, and vary according to genotype. New paradigms, possibly involving nutrigenomic tools, will be necessary to optimise the forms and levels of Se desirable for maximum protection of genomic stability in all humans.     

H2AX haploinsufficiency modifies genomic stability and tumor susceptibility

Histone H2AX becomes phosphorylated in chromatin domains flanking sites of DNA double-strand breakage associated with gamma-irradiation, meiotic recombination, DNA replication, and antigen receptor rearrangements. Here, we show that loss of a single H2AX allele compromises genomic integrity and enhances the susceptibility to cancer in the absence of p53. In comparison with heterozygotes, tumors arise earlier in the H2AX homozygous null background, and H2AX(-/-) p53(-/-) lymphomas harbor an increased frequency of clonal nonreciprocal translocations and amplifications. These include complex rearrangements that juxtapose the c-myc oncogene to antigen receptor loci. Restoration of the H2AX null allele with wild-type H2AX restores genomic stability and radiation resistance, but this effect is abolished by substitution of the conserved serine phosphorylation sites in H2AX with alanine or glutamic acid residues. Our results establish H2AX as genomic caretaker that requires the function of both gene alleles for optimal protection against tumorigenesis.     

UVRAG: At the crossroad of autophagy and genomic stability

UVRAG is a promoter of the autophagy pathway, and its deficiency may fuel the development of cancers. Intriguingly, our recent study has demonstrated that this protein also mediates the repair of damaged DNA and patrols centrosome stability, mechanisms that commonly prevent cancer progression, in a manner independent of its role in autophagy signaling. Given the central role of UVRAG in genomic stability and autophagic cleaning, it is speculated that UVRAG is a bona fide genome protector and that the decrease in UVRAG seen in some cancers may render these cells vulnerable to chromosomal damage, making UVRAG an appealing target for cancer therapy.