Mutation Research-Reviews in Mutation Research最新文献

{"title":"Mitotic syndicates Aurora Kinase B (AURKB) and mitotic arrest deficient 2 like 2 (MAD2L2) in cohorts of DNA damage response (DDR) and tumorigenesis","authors":"Rahaba Marima ,&nbsp;Rodney Hull ,&nbsp;Clement Penny ,&nbsp;Zodwa Dlamini","doi":"10.1016/j.mrrev.2021.108376","DOIUrl":"10.1016/j.mrrev.2021.108376","url":null,"abstract":"<div><p>Aurora Kinase B (AURKB) and Mitotic Arrest Deficient 2 Like 2 (MAD2L2) are emerging anticancer therapeutic targets. AURKB and MAD2L2 are the least well studied members of their protein families, compared to AURKA and MAD2L1. Both AURKB and MAD2L2 play a critical role in mitosis, cell cycle checkpoint, DNA damage response (DDR) and normal physiological processes. However, the oncogenic roles of AURKB and MAD2L2 in tumorigenesis and genomic instability have also been reported. DDR acts as an arbitrator for cell fate by either repairing the damage or directing the cell to self-destruction. While there is strong evidence of interphase DDR, evidence of mitotic DDR is just emerging and remains largely unelucidated. To date, inhibitors of the DDR components show effective anti-cancer roles. Contrarily, long-term resistance towards drugs that target only one DDR target is becoming a challenge. Targeting interactions between protein-protein or protein-DNA holds prominent therapeutic potential. Both AURKB and MAD2L2 play critical roles in the success of mitosis and their emerging roles in mitotic DDR cannot be ignored. Small molecule inhibitors for AURKB are in clinical trials. A few lead compounds towards MAD2L2 inhibition have been discovered. Targeting mitotic DDR components and their interaction is emerging as a potent next generation anti-cancer therapeutic target. This can be done by developing small molecule inhibitors for AURKB and MAD2L2, thereby targeting DDR components as anti-cancer therapeutic targets and/or targeting mitotic DDR. This review focuses on AURKB and MAD2L2 prospective synergy to deregulate the p53 DDR pathway and promote favourable conditions for uncontrolled cell proliferation.</p></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"787 ","pages":"Article 108376"},"PeriodicalIF":5.3,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.mrrev.2021.108376","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39059048","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD44 polymorphisms and its variants, as an inconsistent marker in cancer investigations","authors":"Mohammad Mahmoudi Gomari ,&nbsp;Marziye Farsimadan ,&nbsp;Neda Rostami ,&nbsp;Zahra mahmoudi ,&nbsp;Mahmood Fadaie ,&nbsp;Ibrahim Farhani ,&nbsp;Parastoo Tarighi","doi":"10.1016/j.mrrev.2021.108374","DOIUrl":"10.1016/j.mrrev.2021.108374","url":null,"abstract":"<div><p>Among cell surface markers<span><span>, CD44 is considered the main marker for identifying and isolating the </span>cancer stem cells<span> (CSCs) among other cells and has attracted significant attention in a variety of research areas. Many studies have shown the essential roles of CD44 in initiation, metastasis, and tumorigenesis in different types of cancer; however, the validity of CD44 as a therapeutic or diagnostic target has not been fully confirmed in some other studies. Whereas the association of specific single nucleotide polymorphisms (SNPs) in the CD44 gene and related variants with cancer risk have been observed in clinical investigations, the significance of these findings remains controversial. Here, we aimed to provide an up-to-date overview of recent studies on the association of CD44 polymorphisms and its variants with different kinds of cancer to determine whether or not it can be used as an appropriate candidate for cancer tracking.</span></span></p></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"787 ","pages":"Article 108374"},"PeriodicalIF":5.3,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.mrrev.2021.108374","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39059049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Function and molecular mechanisms of APE2 in genome and epigenome integrity","authors":"Yunfeng Lin ,&nbsp;Anne McMahon ,&nbsp;Garrett Driscoll ,&nbsp;Sharon Bullock ,&nbsp;Jianjun Zhao ,&nbsp;Shan Yan","doi":"10.1016/j.mrrev.2020.108347","DOIUrl":"10.1016/j.mrrev.2020.108347","url":null,"abstract":"<div><p>APE2 is a rising vital player in the maintenance of genome and epigenome integrity. In the past several years, a series of studies have shown the critical roles and functions of APE2. We seek to provide the first comprehensive review on several aspects of APE2 in genome and epigenome integrity. We first summarize the distinct functional domains or motifs within APE2 including EEP (endonuclease/exonuclease/phosphatase) domain, PIP box and Zf-GRF motifs from eight species (<em>i.e.</em>, <em>Homo sapiens</em>, <em>Mus musculus</em>, <em>Xenopus laevis</em>, <em>Ciona intestinalis</em>, <em>Arabidopsis thaliana</em>, <em>Schizosaccharomyces pombe</em>, <em>Saccharomyces cerevisiae</em>, and <em>Trypanosoma cruzi</em>). Then we analyze various APE2 nuclease activities and associated DNA substrates, including AP endonuclease, 3′-phosphodiesterase, 3′-phosphatase, and 3′-5′ exonuclease activities. We also examine several APE2 interaction proteins, including PCNA, Chk1, APE1, Myh1, and homologous recombination (HR) factors such as Rad51, Rad52, BRCA1, BRCA2, and BARD1. Furthermore, we provide insights into the roles of APE2 in various DNA repair pathways (base excision repair, single-strand break repair, and double-strand break repair), DNA damage response (DDR) pathways (ATR-Chk1 and p53-dependent), immunoglobulin class switch recombination and somatic hypermutation, as well as active DNA demethylation. Lastly, we summarize critical functions of APE2 in growth, development, and diseases. In this review, we provide the first comprehensive perspective which dissects all aspects of the multiple-function protein APE2 in genome and epigenome integrity.</p></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"787 ","pages":"Article 108347"},"PeriodicalIF":5.3,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.mrrev.2020.108347","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39059054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"External modulators and redox homeostasis: Scenario in radiation-induced bystander cells","authors":"Sharmi Mukherjee,&nbsp;Anindita Dutta,&nbsp;Anindita Chakraborty","doi":"10.1016/j.mrrev.2021.108368","DOIUrl":"10.1016/j.mrrev.2021.108368","url":null,"abstract":"<div><p>Redox homeostasis is imperative to maintain normal physiologic and metabolic functions. Radiotherapy disturbs this balance and induces genomic instability in diseased cells. However, radiation-induced effects propagate beyond the targeted cells, affecting the adjacent non-targeted cells (bystander effects). The cellular impact of radiation, thus, encompasses both targeted and non-targeted effects. Use of external modulators along with radiation can increase radio-therapeutic efficiency. The modulators’ classification as protectors or sensitizers depends on interactions with damaged DNA molecules. Thus, it is necessary to realize the functions of various radio-sensitizers or radio-protectors in both irradiated and bystander cells. This review focuses on some modulators of radiation-induced bystander effects (RIBE) and their action mechanisms. Knowledge about the underlying signaling cross-talk may promote selective sensitization of radiation-targeted cells and protection of bystander cells.</p></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"787 ","pages":"Article 108368"},"PeriodicalIF":5.3,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.mrrev.2021.108368","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39056638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The hCOMET project: International database comparison of results with the comet assay in human biomonitoring. Baseline frequency of DNA damage and effect of main confounders","authors":"Mirta Milić ,&nbsp;Marcello Ceppi ,&nbsp;Marco Bruzzone ,&nbsp;Amaya Azqueta ,&nbsp;Gunnar Brunborg ,&nbsp;Roger Godschalk ,&nbsp;Gudrun Koppen ,&nbsp;Sabine Langie ,&nbsp;Peter Møller ,&nbsp;João Paulo Teixeira ,&nbsp;Avdulla Alija ,&nbsp;Diana Anderson ,&nbsp;Vanessa Andrade ,&nbsp;Cristina Andreoli ,&nbsp;Fisnik Asllani ,&nbsp;Ezgi Eyluel Bangkoglu ,&nbsp;Magdalena Barančoková ,&nbsp;Nursen Basaran ,&nbsp;Elisa Boutet-Robinet ,&nbsp;Annamaria Buschini ,&nbsp;Stefano Bonassi","doi":"10.1016/j.mrrev.2021.108371","DOIUrl":"10.1016/j.mrrev.2021.108371","url":null,"abstract":"<div><p>The alkaline comet assay, or single cell gel electrophoresis, is one of the most popular methods for assessing DNA damage in human population. One of the open issues concerning this assay is the identification of those factors that can explain the large inter-individual and inter-laboratory variation. International collaborative initiatives such as the hCOMET project - a COST Action launched in 2016 - represent a valuable tool to meet this challenge. The aims of hCOMET were to establish reference values for the level of DNA damage in humans, to investigate the effect of host factors, lifestyle and exposure to genotoxic agents, and to compare different sources of assay variability. A database of 19,320 subjects was generated, pooling data from 105 studies run by 44 laboratories in 26 countries between 1999 and 2019. A mixed random effect log-linear model, in parallel with a classic meta-analysis, was applied to take into account the extensive heterogeneity of data, due to descriptor, specimen and protocol variability. As a result of this analysis interquartile intervals of DNA strand breaks (which includes alkali-labile sites) were reported for tail intensity, tail length, and tail moment (comet assay descriptors). A small variation by age was reported in some datasets, suggesting higher DNA damage in oldest age-classes, while no effect could be shown for sex or smoking habit, although the lack of data on heavy smokers has still to be considered. Finally, highly significant differences in DNA damage were found for most exposures investigated in specific studies. In conclusion, these data, which confirm that DNA damage measured by the comet assay is an excellent biomarker of exposure in several conditions, may contribute to improving the quality of study design and to the standardization of results of the comet assay in human populations.</p></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"787 ","pages":"Article 108371"},"PeriodicalIF":5.3,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.mrrev.2021.108371","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39058066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Micronuclei, reproduction and child health","authors":"Lisbeth E. Knudsen ,&nbsp;Micheline Kirsch-Volders","doi":"10.1016/j.mrrev.2020.108345","DOIUrl":"10.1016/j.mrrev.2020.108345","url":null,"abstract":"<div><p>The current review looks for relationships between results from biomarker studies with micronucleus and health effects related to reproduction and children. In adults, an age related increase in MN is well known as well as associations with environmental exposures especially air pollution from traffic and smoking.</p><p>Literature searches in PubMED and SCOPUS were performed with the following keywords reproduction, children, micronuclei, health effects. In total 162 studies were identified with the keyword children. Concerning children and health and children and environmental exposures, the titles and abstracts of a total of 162 publications were screened for language, inclusion of data from children and selected according to a study selection chart. 9 studies were included for children and health, and 21 studies for children and environmental exposures, with 12 in buccal cells and 9 in lymphocytes. The publications were read and included in tables if data on controls was available.</p><p>MN frequencies were collected for peripheral blood lymphocytes (PBLs), reticulocytes or buccal cells (BC) and reported as Mean ± SD or Median (IQR). The Mean frequency Ratio, MRi, corresponding to the MN mean for study persons divided by MN mean for control persons was stated as reported in the publication or calculated by us from the data in the publication, where possible.</p><p>Our systematic analysis revealed a number of positive associations of MN frequencies as a marker of increased health risk in relation to reproduction as well as child health. The majority of studies reported with children concerns exposures of children as well as maternal exposures and newborn health with MN as a biomarker of exposure. Exposure monitoring by MN as biomarker is also reported in studies of school children however most often not related to health effects. The MRis are found in ranges from 1 to 5.5 most studies around 2.</p><p>As far as MN frequencies in children and exposure are concerned, the MRis range from 0.9 to 5.5, with a range from 1.3–4.9 for lymphocytes and from 1.5 to 2.5 in buccal cells, except for two studies with no differences found between cases and controls. Only one study is available for MRi calculation in reticulocytes with the value of 2.3.</p><p>These data are supporting MN as a relevant biomarker for children health. However, the data is mostly from small studies with different protocol leaving out the possibility of metanalyses and even statistical comparisons among studies. The actual risk from elevated MNs in children waits large cohort studies with pooled datasets as performed with MN measured in adults.</p><p>Introduction of buccal cells as non invasive alternative to lymphocytes is increasing and as with the lymphocytes standardised protocols are recommended to enable comparative studies and metaanalyses.</p></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"787 ","pages":"Article 108345"},"PeriodicalIF":5.3,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.mrrev.2020.108345","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39058067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential application of γ-H2AX as a biodosimetry tool for radiation triage","authors":"Venkateswarlu Raavi ,&nbsp;Venkatachalam Perumal ,&nbsp;Solomon F.D. Paul","doi":"10.1016/j.mrrev.2020.108350","DOIUrl":"10.1016/j.mrrev.2020.108350","url":null,"abstract":"<div><p>Radiation triage and biological dosimetry<span><span> are two initial steps in the medical management of exposed individuals following radiological accidents. Well established biodosimetry methods such as the dicentric (DC) assay, micronucleus (MN) assay, and fluorescence in-situ hybridization (FISH) translocation assay (for residual damage) have been used for this purpose for several decades. Recent advances in scoring methodology and networking among established laboratories have increased triage capacity; however, these methods still have limitations in analysing large sample numbers, particularly because of the ∼ 48 h minimum culture time required prior to analysis. Hence, there is a need for simple, and high throughput markers to identify exposed individuals in case of radiological/nuclear emergencies. In recent years, a few markers were identified, one being phosphorylated histone 2AX (γ-H2AX), which measured a nuclear foci or nuclear staining intensity that was found to be suitable for triage. Measurement of γ-H2AX foci formed at and around the sites of </span>DNA double-strand breaks is a rapid and sensitive biodosimetry method which does not require culturing and is thus promising for the analysis of a large number of samples. In this review, we have summarized the recent developments of γ-H2AX assay in radiation triage and biodosimetry, focusing chiefly on: i) the importance of baseline frequency and reported values among different laboratories, ii) the influence of known and unknown variables on dose estimation, iii) quality assurance such as inter-laboratory comparison between scorers and scoring methods, and iv) current limitations and potential for future development.</span></p></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"787 ","pages":"Article 108350"},"PeriodicalIF":5.3,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.mrrev.2020.108350","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39059052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of infections, preneoplasia and cancer on micronucleus formation in urothelial and cervical cells: A systematic review","authors":"T. Setayesh ,&nbsp;A. Nersesyan ,&nbsp;M. Kundi ,&nbsp;M. Mišík ,&nbsp;M. Fenech ,&nbsp;C. Bolognesi ,&nbsp;H. Stopper ,&nbsp;G. Parsadanyan ,&nbsp;B. Ernst ,&nbsp;S. Knasmueller","doi":"10.1016/j.mrrev.2020.108361","DOIUrl":"10.1016/j.mrrev.2020.108361","url":null,"abstract":"<div><p>Approximately 165,000 and 311,000 individuals die annually from urothelial (UC) and cervical (CC) cancer. The therapeutic success of these cancers depends strongly on their early detection and could be improved by use of additional diagnostic tools. We evaluated the current knowledge of the use of micronucleus (MN) assays (which detect structural and numerical chromosomal aberrations) with urine- (UDC) and cervix-derived (CDC) cells for the identification of humans with increased risks and for the diagnosis of UC and CC. Several findings indicate that MN rates in UDC are higher in individuals with inflammation and schistosomiasis that are associated with increased prevalence of UC; furthermore, higher MN rates were also found in CDC in women with HPV<span><span>, Candidiasis<span> and Trichomonas<span> infections which increase the risks for CC. Only few studies were published on MN rates in UDS in patients with UC, two concern the detection of recurrent bladder tumors. Strong correlations were found in individuals with abnormal CC cells that are scored in Pap tests and histopathological abnormalities. In total, 16 studies were published which concerned these topics. MN rates increased in the order: inflammation &lt; ASC-US/ASC-H &lt; LSIL &lt; HSIL &lt; CC. It is evident that MNi numbers increase with the risk to develop CC and with the degree of </span></span></span>malignant transformation. Overall, the evaluation of the literature indicates that MNi are useful additional biomarkers for the prognosis and detection of CC and possibly also for UC. In regard to the diagnosis/surveillance of UC, further investigations are needed to draw firm conclusions, but the currently available data are promising. In general, further standardization of the assays is needed (i.e. definition of optimal cell numbers and of suitable stains as well as elucidation of the usefulness of parameters reflecting cytotoxicity and mitotic activity) before MN trials can be implemented in routine screening.</span></p></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"787 ","pages":"Article 108361"},"PeriodicalIF":5.3,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.mrrev.2020.108361","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39074429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interplay between DNA replication stress, chromatin dynamics and DNA-damage response for the maintenance of genome stability","authors":"Maddalena Mognato ,&nbsp;Susanne Burdak-Rothkamm ,&nbsp;Kai Rothkamm","doi":"10.1016/j.mrrev.2020.108346","DOIUrl":"10.1016/j.mrrev.2020.108346","url":null,"abstract":"<div><p>DNA replication stress is a major source of DNA damage, including double-stranded breaks that promote DNA damage response (DDR) signaling. Inefficient repair of such lesions can affect genome integrity. During DNA replication different factors act on chromatin remodeling in a coordinated way. While recent studies have highlighted individual molecular mechanisms of interaction, less is known about the orchestration of chromatin changes under replication stress. In this review we attempt to explore the complex relationship between DNA replication stress, DDR and genome integrity in mammalian cells, taking into account the role of chromatin disposition as an important modulator of DNA repair. Recent data on chromatin restoration and epigenetic re-establishment after DNA replication stress are reviewed.</p></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"787 ","pages":"Article 108346"},"PeriodicalIF":5.3,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.mrrev.2020.108346","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39058070","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relationships among smoking, oxidative stress, inflammation, macromolecular damage, and cancer","authors":"Andrew W. Caliri,&nbsp;Stella Tommasi,&nbsp;Ahmad Besaratinia","doi":"10.1016/j.mrrev.2021.108365","DOIUrl":"10.1016/j.mrrev.2021.108365","url":null,"abstract":"<div><p>Smoking is a major risk factor for a variety of diseases, including cancer and immune-mediated inflammatory diseases. Tobacco smoke contains a mixture of chemicals, including a host of reactive oxygen- and nitrogen species (ROS and RNS), among others, that can damage cellular and sub-cellular targets, such as lipids, proteins, and nucleic acids. A growing body of evidence supports a key role for smoking-induced ROS and the resulting oxidative stress in inflammation and carcinogenesis. This comprehensive and up-to-date review covers four interrelated topics, including <em>‘smoking’</em>, <em>‘oxidative stress’</em>, <em>‘inflammation’</em>, and <em>‘cancer’</em><span>. The review discusses each of the four topics, while exploring the intersections among the topics by highlighting the macromolecular damage attributable to ROS. Specifically, oxidative damage to macromolecular targets, such as lipid peroxidation, post-translational modification of proteins, and DNA adduction, as well as enzymatic and non-enzymatic antioxidant defense mechanisms, and the multi-faceted repair pathways of oxidized lesions are described. Also discussed are the biological consequences of oxidative damage to macromolecules if they evade the defense mechanisms and/or are not repaired properly or in time. Emphasis is placed on the genetic- and epigenetic alterations that may lead to transcriptional deregulation of functionally-important genes and disruption of regulatory elements. Smoking-associated oxidative stress also activates the inflammatory response pathway, which triggers a cascade of events of which ROS production is an initial yet indispensable step. The release of ROS at the site of damage and inflammation helps combat foreign pathogens and restores the injured tissue, while simultaneously increasing the burden of oxidative stress. This creates a vicious cycle in which smoking-related oxidative stress causes inflammation, which in turn, results in further generation of ROS, and potentially increased oxidative damage to macromolecular targets that may lead to cancer initiation and/or progression.</span></p></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"787 ","pages":"Article 108365"},"PeriodicalIF":5.3,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.mrrev.2021.108365","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39059050","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}