Engineering a DNA damage response without DNA damage

Recent work has achieved the feat of activating the DNA damage checkpoint in the absence of DNA damage, revealing the importance of protein-chromatin associations for the activation, amplification and maintenance of the DNA damage response.     

Hereditary damage

Summary For the purposes of radiation protection, risk estimates should be based on effects of irradiation at low doses and low dose-rates. Although few genetic studies have been made on effects at low doses those carried out at low dose-rates suggest that the response is generally linear for induction of both gene mutations and chromosome aberrations. For obtaining an overall genetic risk assessment under these conditions a doubling dose of 100 rem (1 Sv) has been used by the ICRP and other bodies, with respect to radiation of low LET. In addition, it is necessary to know frequencies of human hereditary conditions, the extent to which these frequencies are maintained by recurrent mutation and the average number of generations the different categories of hereditary damage persist in the population. By the use of this information, as well as some data on translocation induction obtained directly from human exposures, an estimate of the risk of serious hereditary ill health in the first two generations after low-level radiation exposure was obtained for the Commission by one of its task groups. Thus the estimate of 10^–2 Sv^–1 used in ICRP 26 has a factual basis, although a number of far-reaching assumptions have still to be made when any risk estimation of this nature is attempted.Invited paper, presented at the 14th Annual Meeting of European Society of Radiation Biology, Jülich, Germany, October 8–14, 1978     

Radiation damage to dinucleoside monophosphates: mediated versus direct damage

The mediation of radiation-induced damage to dinucleoside monophosphate by oxygen and by glutathione was studied. The sequence isomers d(TpA) and d(ApT) were X-irradiated in aqueous solutions and the products isolated by reverse-phase high-performance liquid chromatography. The main products were characterized by proton NMR spectroscopy. In the presence of oxygen the principal products are the formamido derivative formed by breakdown of thymine and the aldehyde derivative formed at the 5' end of the dinucleoside monophosphate, both nucleoside monophosphates and free bases. In the presence of glutathione, the two stereoisomers of the 5,6-dihydrothymine derivatives are prominent. Radiation-induced damage to d(TpA) and d(ApT) in the solid state was also studied.     

Repairing DNA-methylation damage

Methylating agents modify DNA at many different sites, thereby producing lethal and mutagenic lesions. To remove all the main harmful base lesions, at least three types of DNA-repair activities can be used, each of which involves a different reaction mechanism. These activities include DNA-glycosylases, DNA-methyltransferases and the recently characterized DNA-dioxygenases. The Escherichia coli AlkB dioxygenase and the two human homologues, ABH2 and ABH3, represent a novel mechanism of DNA repair. They use iron-oxo intermediates to oxidize stable methylated bases in DNA and directly revert them to the unmodified form.     

Heat potentiation of radiation damage versus radiation potentiation of heat damage

The enhanced lethality of mammalian cells after combined treatment with hyperthermia and radiation is usually attributed to heat potentiation of radiation damage. However, it has been suggested that the situation may be reversed and that radiation may act as a modifier for heat damage. To test this hypothesis, BP-8 murine sarcoma cells were subjected to sequential radiation and heat treatments and the kinetics and extent of cell death were evaluated with the [125I]-iododeoxyuridine prelabeling assay. Cell death after heating was rapid and essentially complete within 2 days after heat exposure, whereas radiation death was slow and became apparent only after a delay period of 3 days. Combined exposure of cells to radiation and heat caused a pronounced increase in the delayed component of cell death, that is, the radiation component of death. Irradiation of cells before heating did not change the early heat component of cell death even in cells that were exposed to massive radiation doses of up to 300 Gy prior to heating. These results indicate that the increased cell death observed in hyperthermia/radiation-treated cells results from heat potentiation of radiation damage, not radiation potentiation of heat damage.     

Continuum damage mechanics (CDM) modelling demonstrates that ligament fatigue damage accumulates by different mechanisms than creep damage

Ligaments can be subjected to creep and fatigue damage when loaded to higher than normal stresses due to injury of a complementary joint restraint. Continuum damage mechanics (CDM) assumes that diffuse damage accumulates in a material, thereby reducing the effective cross-sectional area and leading to eventual rupture. The objective of this study was to apply CDM modelling to ligament creep and fatigue to reveal mechanisms of damage. Fatigue was modelled by cyclically varying the stress in the creep model. A few novel approaches were used. First, area reduction was not assumed equal to modulus reduction; thus, allowing damaged fibres to potentially contribute to load-bearing through the extracellular matrix. Modulus ratio was related to area reduction using residual strength. Second, damage rate was not assumed constant but rather was determined directly from the modulus ratio change with respect to time. Third, modulus ratio was normalized to maximum modulus to avoid artificial calculation of negative damage. With this approach, the creep time-to-rupture was predicted with -4% error at 60% UTS and -13% error at 30% UTS. At 15% UTS, no test was undertaken experimentally for a duration as long as the 24 days predicted theoretically. Oscillating the time-dependent damage in the creep model could not completely explain the fatigue behaviour because the fatigue time-to-rupture was predicted with over 1300% error at all stresses. These results suggest that a cycle-dependent damage mechanism, in addition to a time-dependent one, was responsible for fatigue rupture. Cycle-dependent damage may be an important consideration for rehabilitation activities following injury of a complementary ligament restraint.     

Role of DNA damage in the formation of radiation damage to chromosomes

The data are reviewed on the role of various DNA lesions in the formation of structural damages to chromosomes. The concepts are developed that the molecular damages to nuclear DNA induce chromosome mutagenesis.     

太行山东北部区域野生动物损害及损害补偿

人兽冲突是生物多样性保护的重要研究主题,合理的损害补偿有助于野生动物可持续保护及管理。为探究太行山东北部区域野生动物损害及损害补偿,于2019年与2020年7—9月对区域内主要肇事野生动物(野猪Sus scrofa和狗獾Meles leucurus)进行了种群及损害调查;2021年7—8月基于访谈,对区域的损害赔偿及社区的受偿意愿进行了量化计测和分析。结果表明,太行山东北部区域的野猪(密度为(6.283±1.274)只/km²)及狗獾(密度为(4.855±1.610)只/km²)种群较大,对区域内的农业生产带来了较大损害,且肇事频率呈上升趋势;已有的防控手段效果有限,当地社区对野生动物保护支持度较高,但对肇事动物保护的态度相对消极;区域内的野生动物损害补偿已普遍施行,有效补偿了受损农户的部分经济损失,但也存在补偿覆盖不全面、补偿标准模糊及补偿数额偏低等问题。当地农户的受偿意愿((10962.60±1751.55)元/hm²)与其文化程度、损害补偿满意度和野生动物保护态度负相关,与保护政策支持度正相关。根据调研结果,建议加...     

How tissue damage MET metabolism: Regulation of the systemic damage response

Living organisms experience tissue damage from both, the surrounding environment and from inside their bodies. Tissue repair/regeneration is triggered by local tissue injury to restore an injured, or lost, part of the body. Tissue damage results in a series of responses, not only locally but also systemically in distant tissues. In our recent publication, we established a “dual system” that induces spatiotemporal tissue damage simultaneously with gene manipulation in surrounding tissues. With this system, we demonstrated that appropriate regulation of methionine metabolism in the fat body is required for tissue repair in Drosophila wing discs, thus highlighting the importance of systemic damage response (SDR) in tissue repair. This “Extra View” aims to discuss our recent reports that propose methionine metabolism to be an essential part of SDR, together with related topics in several model organisms.     

DNA damage by mycotoxins

Mycotoxins are toxic fungal metabolites which are structurally diverse, common contaminants of the ingredients of animal feed and human food. To date, mycotoxins with carcinogenic potency in experimental animal models include aflatoxins, sterigmatocystin, ochratoxin, fumonisins, zearalenone, and some Penicillium toxins. Most of these carcinogenic mycotoxins are genotoxic agents with the exception of fumonisins, which is currently believed to act by disrupting the signal transduction pathways of the target cells. Aflatoxin B1 (AFB1), a category I known human carcinogen and the most potent genotoxic agent, is mutagenic in many model systems and produces chromosomal aberrations, micronuclei, sister chromatid exchange, unscheduled DNA synthesis, and chromosomal strand breaks, as well as forms adducts in rodent and human cells. The predominant AFB1-DNA adduct was identified as 8, 9-dihydro-8-(N7-guanyl)-9-hydroxy-AFB1 (AFB1-N7-Gua), which derives from covalent bond formation between C8 of AFB1-8,9-epoxides and N7 of guanine bases in DNA. Initial AFB1-N7-guanine adduct can convert to a ring-opened formamidopyrimidine derivative, AFB1-FAPY. The formation of AFB1-N7-guanine adduct was linear over the low-dose range in all species examined, and liver, the primary target organ, had the highest level of the adduct. Formation of initial AFB1-N7-guanine adduct was correlated with the incidence of hepatic tumor in trout and rats. The AFB1-N7-guanine adduct was removed from DNA rapidly and was excreted exclusively in urine of exposed rats. Several human studies have validated the similar correlation between dietary exposure to AFB1 and excretion of AFB1-N7-guanine in urine. Replication of DNA containing AFB1-N7-guanine adduct-induced G-->T mutations in an experimental model. Activation of ras protooncogene has been found in AFB1-induced tumors in mouse, rat, and fish. More strikingly, the relationship between aflatoxin exposure and development of human hepatocellular carcinoma (HHC) was demonstrated by the studies on the p53 tumor suppressor gene. High frequency of p53 mutations (G-->T transversion at codon 249) was found to occur in HHC collected from populations exposed to high levels of dietary aflatoxin in China and Southern Africa. Furthermore, AFB1-induced DNA damage and hepatocarcinogenesis in experimental models can be modulated by a variety of factors including nutrients, chemopreventive agents, and other factors such as food restriction and viral infection, as well as genetic polymorphisms.