查看更多>>摘要：The human genome is continuously exposed to such potentially deleterious agents as the highly reactive molecules known as reactive oxygen species (ROS)。 ROS include superoxide anions (O(2)(-)) and hydrogen peroxide (H(2)O(2))。 Over the last decade， the ROS-generating NADPH oxidases (NOXs) have been recognized as one of the main sources of ROS production in numerous human cell types。 In addition to regulating normal physiological redox-dependent processes， the NOXs are involved in cellular oxidative stress。 In contrast to the other NOXs， the NADPH oxidase NOX4 exists in the immediate environment of the nucleus。 There is accumulating evidence for the involvement of NOX4-derived ROS in genomic instability as well as in cancer and other inflammation-related diseases。 We recently showed that NOX4 plays a critical role in oncogenic Ras-induced DNA damage。 Here we reflect upon the growing awareness of NOX4， review its role in inducing genomic instability， and call attention to its possible role in nuclear redox-sensitive mechanisms underlying DNA-damage signaling and repair。
查看更多>>摘要：Di(ethylhexyl) phthalate (DEHP) is a manufactured chemical commonly added to plastics: it is a ubiquitous environmental contaminant to which humans are exposed through multiple routes。 DEHP is a rodent carcinogen with an extensive data base on genotoxicity and related effects spanning several decades。 Although DEHP has been reported to be negative in most non-mammalian in vitro mutation assays， most studies were performed under conditions of concurrent cytotoxicity， precipitation， or irrelevant metabolic activation。 However， a number of in vitro rodent tissue assays have reported DEHP to be positive for effects on chromosomes， spindle， and mitosis。 A robust database shows that DEHP increases transformation and inhibits apoptosis in Syrian hamster embryo cells。 In a transgenic mouse assay， in vivo DEHP exposure increased the mutation frequency only in the liver， which is the target organ for cancer。 In vitro exposure of human cells or tissues to DEHP induced DNA damage; altered mitotic rate， apoptosis， and cell proliferation; increased proliferation， tumor mobility， and invasiveness of tumor cell lines; and activated a number of nuclear receptors。 DEHP has been shown to be an agonist for CAR2， a novel constitutive androstane receptor occurring only in humans。 Environmental exposures of humans to DEHP have been associated with DNA damage。 After taking into account study context and relevant issues affecting interpretation， in vitro studies reported that a similar DEHP concentration range induced both mutagenic and non-mutagenic effects in human tissues and， using a much more limited rodent database， transformation of embryonic rodent tissues。 The human and rodent data suggest that DEHP induces cancer through multiple molecular signals， including DNA damage。 The analyses presented here may provide guidance for similar data sets used in structure-activity relationships， computational-toxicology extrapolations， and attempts to extrapolate in vitro results to predict in vivo effects for hazard characterization。
查看更多>>摘要：The faithful maintenance of chromosome continuity in human cells during DNA replication and repair is critical for preventing the conversion of normal diploid cells to an oncogenic state。 The evolution of higher eukaryotic cells endowed them with a large genetic investment in the molecular machinery that ensures chromosome stability。 In mammalian and other vertebrate cells， the elimination of double-strand breaks with minimal nucleotide sequence change involves the spatiotemporal orchestration of a seemingly endless number of proteins ranging in their action from the nucleotide level to nucleosome organization and chromosome architecture。 DNA DSBs trigger a myriad of post-translational modifications that alter catalytic activities and the specificity of protein interactions: phosphorylation， acetylation， methylation， ubiquitylation， and SUMOylation， followed by the reversal of these changes as repair is completed。 "Superfluous" protein recruitment to damage sites， functional redundancy， and alternative pathways ensure that DSB repair is extremely efficient， both quantitatively and qualitatively。 This review strives to integrate the information about the molecular mechanisms of DSB repair that has emerged over the last two decades with a focus on DSBs produced by the prototype agent ionizing radiation (IR)。 The exponential growth of molecular studies， heavily driven by RNA knockdown technology， now reveals an outline of how many key protein players in genome stability and cancer biology perform their interwoven tasks， e。g。 ATM， ATR， DNA-PK， Chk1， Chk2， PARP1/2/3， 53BP1， BRCA1， BRCA2， BLM， RAD51， and the MRE11-RAD50-NBS1 complex。 Thus， the nature of the intricate coordination of repair processes with cell cycle progression is becoming apparent。 This review also links molecular abnormalities to cellular pathology as much a possible and provides a framework of temporal relationships。
查看更多>>摘要：Programmed cell death and DNA repair are two fundamental biological processes that play essential roles in cell fate and genetic transmission。 The canonical role of Bcl-2 family members is the regulation of programmed cell death。 Strikingly， numerous studies from different laboratories have shown that although Bcl-2 increases cell survival， it also inhibits all DNA repair systems， resulting in genome instability/variability。 Bcl-2 affects the mechanistically distinct DNA repair systems via different mechanisms。 These effects are generally independent of the regulation of apoptosis， revealing additional roles for Bcl-2。 The targets of Bcl-2 include APE1， MSH2， PARP1， Ku70 and the oncosuppressor BRCA1。 Targetting BRCA1 should be of particular importance because this might impact many essential cellular processes in which BRCA1 is involved， including homologous recombination (HR)， non-homologous end joining (NHEJ)， base excision repair， cell-cycle regulation， cell death， ubiquitination， inactivation of the X-chromosome， transcription， and protein translation。 Beside the pathological consequences， inhibition of DNA repair by Bcl-2 can be， in contrast， advantageously used in some physiological situations: (1) repression of excessive unschedule HR， thus protecting against the accumulation of toxic HR intermediates and HR-dependent genome rearrangements; (2) inhibition of NHEJ might protect against retrovirus integration; (3) it has been proposed that inhibition of mismatch repair might also favors hypermutation at immunoglobulin genes。 Finally， because Bcl-2 affects the maintenance of genome stability， one can suggest Bcl-2 might play a role in molecular evolution。 Bcl-2 family members control cell death through complex stochiometric equilibriums。 Incorporating DNA repair proteins to such an elaborate network should allow for a fine tuning of the coordinated control of cell viability and genetic stability/instability。 Relationships between DNA repair and regulation of cell death represent exciting challenges for future prospects and are essential for the development of promising new strategies against cancer。
Carita LindholmRadhia MkacherRoel QuintensKai Rothkamm...
29页
查看更多>>摘要：Ionizing radiation is a known human carcinogen that can induce a variety of biological effects depending on the physical nature， duration， doses and dose-rates of exposure。 However， the magnitude of health risks at low doses and dose-rates (below 100mSv and/or 0。1mSvmin(-1)) remains controversial due to a lack of direct human evidence。 It is anticipated that significant insights will emerge from the integration of epidemiological and biological research， made possible by molecular epidemiology studies incorporating biomarkers and bioassays。 A number of these have been used to investigate exposure， effects and susceptibility to ionizing radiation， albeit often at higher doses and dose rates， with each reflecting time-limited cellular or physiological alterations。 This review summarises the multidisciplinary work undertaken in the framework of the European project DoReMi (Low Dose Research towards Multidisciplinary Integration) to identify the most appropriate biomarkers for use in population studies。 In addition to logistical and ethical considerations for conducting large-scale epidemiological studies， we discuss the relevance of their use for assessing the effects of low dose ionizing radiation exposure at the cellular and physiological level。 We also propose a temporal classification of biomarkers that may be relevant for molecular epidemiology studies which need to take into account the time elapsed since exposure。 Finally， the integration of biology with epidemiology requires careful planning and enhanced discussions between the epidemiology， biology and dosimetry communities in order to determine the most important questions to be addressed in light of pragmatic considerations including the appropriate population to be investigated (occupationally， environmentally or medically exposed)， and study design。 The consideration of the logistics of biological sample collection， processing and storing and the choice of biomarker or bioassay， as well as awareness of potential confounding factors， are also essential。
Vernon E SteeleSilvio De FloraAlberto IzzottiCristina Cartiglia...
17页
查看更多>>摘要：MicroRNAs (miRNAs) have been implicated in many biological processes， cancer， and other diseases。 In addition， miRNAs are dysregulated following exposure to toxic and genotoxic agents。 Here we review studies evaluating modulation of miRNAs by dietary and pharmacological agents， which could potentially be exploited for inhibition of mutagenesis and carcinogenesis。 This review covers natural agents， including vitamins， oligoelements， polyphenols， isoflavones， indoles， isothiocyanates， phospholipids， saponins， anthraquinones and polyunsaturated fatty acids， and synthetic agents， including thiols， nuclear receptor agonists， histone deacetylase inhibitors， antiinflammatory drugs， and selective estrogen receptor modulators。 As many as 145 miRNAs， involved in the control of a variety of carcinogenesis mechanisms， were modulated by these agents， either individually or in combination。 Most studies used cancer cells in vitro with the goal of modifying their phenotype by changing miRNA expression profiles。 In vivo studies evaluated regulation of miRNAs by chemopreventive agents in organs of mice and rats， either untreated or exposed to carcinogens， with the objective of evaluating their safety and efficacy。 The tissue specificity of miRNAs could be exploited for the chemoprevention of site-specific cancers， and the study of polymorphic miRNAs is expected to predict the individual response to chemopreventive agents as a tool for developing new prevention strategies。
Joris DelangheMarijn SpeeckaertLien Van De VoordeReinhart Speeckaert...
22页
查看更多>>摘要：Alterations of genetic and epigenetic features can provide important insights into the natural history of breast cancer。 Although DNA methylation analysis is a rapidly developing field， a reproducible epigenetic blood-based assay for diagnosis and follow-up of breast cancer has yet to be successfully developed into a routine clinical test。 The aim of this study was to review multiple serum DNA methylation assays and to highlight the value of those novel biomarkers in diagnosis， prognosis and prediction of therapeutic outcome。 Serum is readily accessible for molecular diagnosis in all individuals from a peripheral blood sample。 The list of hypermethylated genes in breast cancer is heterogeneous and no single gene is methylated in all breast cancer types。 There is increasing evidence that a panel of epigenetic markers is essential to achieve a higher sensitivity and specificity in breast cancer detection。 However， the reported percentages of methylation are highly variable， which can be partly explained by the different sensitivities and the different intra-/inter-assay coefficients of variability of the analysis methods。 Moreover， there is a striking lack of receiver operating characteristic (ROC) curves of the proposed biomarkers。 Another point of criticism is the fact that 'normal' patterns of DNA methylation of some tumor suppressor and other cancer-related genes are influenced by several factors and are often poorly characterized。 A relatively frequent methylation of those genes has been observed in high-risk asymptomatic women。 Finally， there is a call for larger prospective cohort studies to determine methylation patterns during treatment and follow-up。 Identification of patterns specific for a differential response to therapeutic interventions should be useful。 Only in this way， it will be possible to evaluate the predictive and prognostic characteristics of those novel promising biomarkers。
NSTL
Elsevier