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Journal Cover Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
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   Hybrid Journal Hybrid journal (It can contain Open Access articles)
   ISSN (Print) 0027-5107
   Published by Elsevier Homepage  [3042 journals]
  • Ongoing evolution of Pseudomonas aeruginosa PAO1 sublines complicates
           studies of DNA damage repair and tolerance
    • Authors: Julia Sidorenko; Tatjana Jatsenko; Maia Kivisaar
      Pages: 26 - 37
      Abstract: Publication date: Available online 16 March 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Julia Sidorenko, Tatjana Jatsenko, Maia Kivisaar
      Sublines of the major P. aeruginosa reference strain PAO1 are derivatives of the original PAO1 isolate, which are maintained in laboratories worldwide. These sublines display substantial genomic and phenotypic variation due to ongoing microevolution. Here, we examined four sublines, MPAO1, PAO1-L, PAO1-DSM and PAO1-UT, originated from different laboratories, and six DNA polymerase-deficient mutants from the P. aeruginosa MPAO1 transposon library for their employment in elucidation of DNA damage repair and tolerance mechanisms in P. aeruginosa. We found that PAO1 subline PAO1-UT carries a large deletion encompassing the DNA damage inducible imuA-imuB-imuC cassette (PA0669-PA0671), which is implied in mutagenesis in several species. Furthermore, the genetic changes leading to variation in the functionality of the MexEF-OprN efflux system contributed largely to the phenotypic discordance between P. aeruginosa PAO1 sublines. Specifically, we identified multiple mutations in the mexT gene, which encodes a transcriptional regulator of the mexEF-oprN genes, mutations in the mexF, and complete absence of these genes. Of the four tested sublines, MPAO1 was the only subline with the functional MexEF-OprN multidrug efflux system. Active efflux through MexEF-OprN rendered MPAO1 highly resistant to chloramphenicol and ciprofloxacin. Moreover, the functions of specialized DNA polymerase IV and nucleotide excision repair (NER) in 4-NQO-induced DNA damage tolerance appeared to be masked in MPAO1, while were easily detectable in other sublines. Finally, the frequencies of spontaneous and MMS-induced Rifr mutations were also significantly lower in MPAO1 in comparison to the PAO1 sublines with impaired MexEF-OprN efflux system. The MexEF-OprN-attributed differences were also observed between MPAO1 and MPAO1-derived transposon mutants from the two-allele transposon mutant collection. Thus, the accumulating mutations and discordant phenotypes of the PAO1 derivatives challenge the reproducibility and comparability of the results obtained with different PAO1 sublines and also limit the usage of the MPAO1 transposon library in DNA damage tolerance and mutagenesis studies.

      PubDate: 2017-03-21T06:13:29Z
      DOI: 10.1016/j.mrfmmm.2017.03.005
      Issue No: Vol. 797-799 (2017)
  • Cyto-genotoxic and DNA methylation changes induced by different crystal
           phases of TiO2-np in bronchial epithelial (16-HBE) cells
    • Authors: Manosij Ghosh; Deniz ├ľner; Radu-Corneliu Duca; Stevan M. Cokic; Sven Seys; Stef Kerkhofs; Kirsten Van Landuyt; Peter Hoet; Lode Godderis
      Pages: 1 - 12
      Abstract: Publication date: February 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 796
      Author(s): Manosij Ghosh, Deniz Öner, Radu-Corneliu Duca, Stevan M. Cokic, Sven Seys, Stef Kerkhofs, Kirsten Van Landuyt, Peter Hoet, Lode Godderis
      With the increase in use of TiO2-np, a better understanding of their safety is important. In the present study the effect of different crystal phases of TiO2-np (anatase, rutile and anatase: rutile mixture; 20–26nm) were studied for cyto-genotoxicity and global DNA methylation and hydroxymethylation. Cytotoxic response was observed at a concentration of 25μg/ml for the particles tested. Results of comet and micronucleus (with and without CytB) assays revealed significant genotoxic effect of these particles. Flow cytometry revealed cell cycle arrest in the S-phase. Based on the results, toxicity of the particles could be correlated with their physico-chemical properties (i.e. smaller size and hydrodynamic diameter and larger surface area), anatase form being the most toxic. From the results of the cyto-genotoxicity assays, concentrations were determined for the epigenetic study. Effect on global DNA methylation and hydroxymethylation levels were studied at cyto-genotoxic (25μg/ml), genotoxic (12.5μg/ml) and sub cyto-genotoxic (3.25μg/ml) concentrations using LC–MS/MS analysis. Though no significant changes were observed for 3h treatment schedule; significant hypomethylation were observed at 24h for anatase (significant at 3.25 and 25μg/ml), rutile (significant at 3.25 and 25μg/ml) and anatase: rutile mixture (significant at 25μg/ml) forms. The results suggest that epigenetic changes could occur at sub cyto-genotoxic concentrations. And hence for complete characterization of nanoparticle toxicity, epigenetic studies should be performed along with conventional toxicity testing methods.

      PubDate: 2017-02-16T12:59:25Z
      DOI: 10.1016/j.mrfmmm.2017.01.003
      Issue No: Vol. 796 (2017)
  • A Novel Type of Gene Interaction in D. melanogaster
    • Authors: B.F. Chadov; E.V. Chadova; N.B. Fedorova
      Pages: 27 - 30
      Abstract: Publication date: Available online 11 January 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): B.F. Chadov, E.V. Chadova, N.B. Fedorova
      The genes interact according to classical mechanisms, namely, complementation, modification, polymery, and epistasis, in the cells and organisms carrying these genes. Here we describe a novel type of gene interaction when the interacting genes reside in parents, whereas the interaction event takes place in their progenies lacking these genes. The conditional mutations in the D. melanogaster male X chromosome caused the “prohibition on producing daughters” in its offspring. The chromosomal rearrangements in chromosomes 2 and 3 of its female partner removed the prohibition. The phenomena of “prohibition” and “removal of prohibition” appeared as a parental effect in both the male and female. Both phenomena ensued from the presence of the studied mutations in parents rather than their unviable or survived progenies. Thus, the gene interaction when the genes themselves are absent at the site of interaction and during the interaction event takes place in drosophila.

      PubDate: 2017-01-15T19:04:37Z
      DOI: 10.1016/j.mrfmmm.2017.01.002
      Issue No: Vol. 795 (2017)
  • Regulation of DNA damage tolerance in mammalian cells by
           post-translational modifications of PCNA
    • Authors: Rie Kanao; Chikahide Masutani
      Abstract: Publication date: Available online 21 June 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Rie Kanao, Chikahide Masutani
      DNA damage tolerance pathways, which include translesion DNA synthesis (TLS) and template switching, are crucial for prevention of DNA replication arrest and maintenance of genomic stability. However, these pathways utilize error-prone DNA polymerases or template exchange between sister DNA strands, and consequently have the potential to induce mutations or chromosomal rearrangements. Post-translational modifications of proliferating cell nuclear antigen (PCNA) play important roles in controlling these pathways. For example, TLS is mediated by mono-ubiquitination of PCNA at lysine 164, for which RAD6–RAD18 is the primary E2–E3 complex. Elaborate protein–protein interactions between mono-ubiquitinated PCNA and Y-family DNA polymerases constitute the core of the TLS regulatory system, and enhancers of PCNA mono-ubiquitination and de-ubiquitinating enzymes finely regulate TLS and suppress TLS-mediated mutagenesis. The template switching pathway is promoted by K63-linked poly-ubiquitination of PCNA at lysine 164. Poly-ubiquitination is achieved by a coupled reaction mediated by two sets of E2–E3 complexes, RAD6–RAD18 and MMS2–UBC13–HTLF/SHPRH. In addition to these mono- and poly-ubiquitinations, simultaneous mono-ubiquitinations on multiple units of the PCNA homotrimeric ring promote an unidentified damage tolerance mechanism that remains to be fully characterized. Furthermore, SUMOylation of PCNA in mammalian cells can negatively regulate recombination. Other modifications, including ISGylation, acetylation, methylation, or phosphorylation, may also play roles in DNA damage tolerance and control of genomic stability.

      PubDate: 2017-06-22T13:14:08Z
  • Mut Res special section “Protein modifications in DNA repair and
    • Authors: Minoru Takata
      Abstract: Publication date: Available online 15 June 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Minoru Takata

      PubDate: 2017-06-16T12:54:55Z
      DOI: 10.1016/j.mrfmmm.2017.06.003
  • Editorial
    • Authors: Minoru Takata
      Abstract: Publication date: Available online 10 June 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Minoru Takata

      PubDate: 2017-06-12T12:43:48Z
      DOI: 10.1016/j.mrfmmm.2017.06.001
  • Variable spontaneous mutation rate in clinical strains of
           multidrug-resistant Acinetobacter baumannii and differentially expressed
           proteins in a hypermutator strain
    • Authors: Morteza Karami-Zarandi; Masoumeh Douraghi; Behrouz Vaziri; Habibeh Adibhesami; Mohammad Rahbar; Mehdi Yaseri
      Abstract: Publication date: Available online 8 June 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Morteza Karami-Zarandi, Masoumeh Douraghi, Behrouz Vaziri, Habibeh Adibhesami, Mohammad Rahbar, Mehdi Yaseri
      Background The emergence of multidrug resistant Acinetobacter baumannii within hospitals poses a significant threat to patients. The inherent rate of mutation of these strains has not been described nor has the mechanism by which drug resistance arises. Methods Here, we determined the spontaneous mutation rates in 93 clinical strains of A. baumannii using fluctuation analysis. To rule out the clonal relatedness of hypermutator strains, pulsed-field gel electrophoresis (PFGE) was conducted. Using a combination of two-dimensional gel electrophoresis (2-DE) and MALDI-TOF mass spectrometry, the differentially expressed proteins of a hypermutator and a reference strain were identified. Results The spontaneous mutation rate of multi-drug resistant A. baumannii strains varied broadly from 0 to 2.1×10−6 mutation per cell division. The mutation rate in three multidrug resistant A. baumannii (MDR-AB) strains was found to be 1.63×10−6 (95% confidence interval (CI): 1×10−6–2×10−6), 2.1×10−6 (95% CI: 2×10−6 − 3×10−6), and 1.78×10−8 (95% CI: 9.29×10−9 2.95×10−8), consistent with a hypermutator phenotype. This rate is approximately 1000-fold higher than the average mutation rate in other MDR-ABs. PFGE of the three hypermutator strains indicate that they belong to distinct clones. Proteomic analysis of one hypermutator strain revealed 31 differentially expressed proteins including three with sizes of 51.2, 20.9, and 11.9kDa, which corresponded to a serine protease, a polyisoprenoid-binding protein, and the peptidoglycan binding protein, LysM. The serine protease was expressed only in the hypermutator strain, whereas the polyisoprenoid-binding protein and the peptidoglycan binding protein LysM were down-regulated 1.6 and 3-fold, respectively, in the hypermutators strain. Conclusion Hypermutator A. baumannii strains occur with a low, but appreciable frequency among clinical multi-drug resistant isolates. The presence of hypermutator clinical isolates raises concerns that they may contribute to the failure of antibiotic treatment in infected patients and confound the interpretation of in vitro antibiotic susceptibility testing. The differentially expressed proteins involved in biofilm suppression and oxidative stress response, may represent adaptations derived from the hypermutator phenotype, a hypothesis that needs further testing.

      PubDate: 2017-06-12T12:43:48Z
      DOI: 10.1016/j.mrfmmm.2017.06.002
  • Eukaryotic DNA damage responses: Homologous recombination factors and
           ubiquitin modification
    • Authors: Nam Soo Lee; Soomi Kim; Yong Woo Jung; Hongtae Kim
      Abstract: Publication date: Available online 6 May 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Nam Soo Lee, Soomi Kim, Yong Woo Jung, Hongtae Kim
      To prevent genomic instability disorders, cells have developed a DNA damage response. The response involves various proteins that sense damaged DNA, transduce damage signals, and effect DNA repair. In addition, ubiquitin modifications modulate the signaling pathway depending on cellular context. Among various types of DNA damage, double-stranded breaks are highly toxic to genomic integrity. Homologous recombination (HR) repair is an essential mechanism that fixes DNA damage because of its high level of accuracy. Although factors in the repair pathway are well established, pinpointing the exact mechanisms of repair and devising therapeutic applications requires more studies. Moreover, essential functions of ubiquitin modification in the DNA damage signaling pathway have emerged. In this review, to explore the eukaryotic DNA damage response, we will mention the functions of main factors in the HR repair pathway and ubiquitin modification.

      PubDate: 2017-05-08T09:57:58Z
      DOI: 10.1016/j.mrfmmm.2017.04.003
  • The functional roles of PML nuclear bodies in genome maintenance
    • Authors: Hae Ryung Chang; Anudari Munkhjargal; Myung-Jin Kim; Seon Young Park; Eunyoung Jung; Jae-Ha Ryu; Young Yang; Jong-Seok Lim; Yonghwan Kim
      Abstract: Publication date: Available online 5 May 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Hae Ryung Chang, Anudari Munkhjargal, Myung-Jin Kim, Seon Young Park, Eunyoung Jung, Jae-Ha Ryu, Young Yang, Jong-Seok Lim, Yonghwan Kim
      In the nucleus, there are several membraneless structures called nuclear bodies. Among them, promyelocytic leukemia nuclear bodies (PML-NBs) are involved in multiple genome maintenance pathways including the DNA damage response, DNA repair, telomere homeostasis, and p53-associated apoptosis. In response to DNA damage, PML-NBs are coalesced and divided by a fission mechanism, thus increasing their number. PML-NBs also play a role in repairing DNA double-strand breaks (DSBs) by homologous recombination (HR). Clinically, the dominant negative PML-RARα fusion protein expressed in acute promyelocytic leukemia (APL) inhibits the transactivation of downstream factors and disrupts PML function, revealing the tumor suppressor role of PML-NBs. All-trans retinoic acid and arsenic trioxide treatment has been implemented for promyelocytic leukemia to target the PML-RARα fusion protein. PML-NBs are associated with various factors implicated in genome maintenance, and are found at the sites of DNA damage. Their interaction with proteins such as p53 indicates that PML-NBs may play a significant role in apoptosis and cancer. Decades of research have revealed the importance of PML-NBs in diverse cellular pathways, yet the underlying molecular mechanisms and exact functions of PML-NBs remain elusive. In this review, PML protein modifications and the functional relevance of PML-NB and its associated factors in genome maintenance will be discussed.

      PubDate: 2017-05-08T09:57:58Z
      DOI: 10.1016/j.mrfmmm.2017.05.002
  • Activation of the FA pathway mediated by phosphorylation and
    • Authors: Masamichi Ishiai; Koichi Sato; Junya Tomida; Hiroyuki Kitao; Hitoshi Kurumizaka; Minoru Takata
      Abstract: Publication date: Available online 5 May 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Masamichi Ishiai, Koichi Sato, Junya Tomida, Hiroyuki Kitao, Hitoshi Kurumizaka, Minoru Takata
      Fanconi anemia (FA) is a devastating hereditary condition that impacts genome integrity, leading to clinical features such as skeletal and visceral organ malformations, attrition of bone marrow stem cells, and carcinogenesis. At least 21 proteins, when absent or defective, have been implicated in this disorder, and they together constitute the FA pathway, which functions in detection and repair of, and tolerance to, endogenous DNA damage. The damage primarily handled by the FA pathway has been assumed to be related to DNA interstrand crosslinks (ICLs). The FA pathway is activated upon ICL damage, and a hallmark of this activation is the mono-ubiquitination events of the key FANCD2-FANCI protein complex. Recent data have revealed unexpectedly complex details in the regulation of FA pathway activation by ICLs. In this short review, we summarize the knowledge accumulated over the years regarding how the FA pathway is activated via protein modifications.

      PubDate: 2017-05-08T09:57:58Z
      DOI: 10.1016/j.mrfmmm.2017.05.003
  • Targeted sequencing identifies novel variants involved in Autosomal
           Recessive Hereditary Hearing Loss in Qatari families
    • Authors: Moza K. Alkowari; Diego Vozzi; Shruti Bhagat; Navaneethakrishnan Krishnamoothy; Anna Morgan; Yousra Hayder; Barathy Logendra; Nehal Najjar; Ilaria Gandin; Paolo Gasparini; Ramin Badii; Giorgia Girotto; Khalid Abdulhadi
      Abstract: Publication date: Available online 4 May 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Moza K. Alkowari, Diego Vozzi, Shruti Bhagat, Navaneethakrishnan Krishnamoothy, Anna Morgan, Yousra Hayder, Barathy Logendra, Nehal Najjar, Ilaria Gandin, Paolo Gasparini, Ramin Badii, Giorgia Girotto, Khalid Abdulhadi
      Hereditary hearing loss (HHL) is characterized by a very high genetic heterogeneity. In the Qatari population the role of GJB2, the worldwide HHL major player, seems to be quite limited compared to Caucasian populations. In this study we analysed 18 Qatari families affected by non-syndromic hearing loss using a targeted sequencing approach that allowed us to analyse 81 genes simultaneously. Thanks to this approach, 50% of these families (9 out of 18) resulted positive for the presence of likely causative alleles in 6 different genes: CDH23, MYO6, GJB6, OTOF, TMC1 and OTOA. In particular, 4 novel alleles were detected while the remaining ones were already described to be associated to HHL in other ethnic groups. Molecular modelling has been used to further investigate the role of novel alleles identified in CDH23 and TMC1 genes demonstrating their crucial role in Ca2+ binding and therefore possible functional role in proteins. Present study showed that an accurate molecular diagnosis based on next generation sequencing technologies might largely improve molecular diagnostics outcome leading to benefits for both genetic counseling and definition of recurrence risk.

      PubDate: 2017-05-08T09:57:58Z
      DOI: 10.1016/j.mrfmmm.2017.05.001
  • Eukaryotic DNA replication: Orchestrated action of Multi-subunit protein
    • Authors: Sukhyun Kang; Mi-Sun Kang; Eunjin Ryu; Kyungjae Myung
      Abstract: Publication date: Available online 1 May 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Sukhyun Kang, Mi-Sun Kang, Eunjin Ryu, Kyungjae Myung
      Genome duplication is an essential process to preserve genetic information between generations. The eukaryotic cell cycle is composed of functionally distinct phases: G1, S, G2, and M. One of the key replicative proteins that participate at every stage of DNA replication is the Mcm2-7 complex, a replicative helicase. In the G1 phase, inactive Mcm2-7 complexes are loaded on the replication origins by replication-initiator proteins, ORC and Cdc6. Two kinases, S-CDK and DDK, convert the inactive origin-loaded Mcm2-7 complex to an active helicase, the CMG complex in the S phase. The activated CMG complex begins DNA unwinding and recruits enzymes essential for DNA synthesis to assemble a replisome at the replication fork. After completion of DNA synthesis, the inactive CMG complex on the replicated DNA is removed from chromatin to terminate DNA replication. In this review, we will discuss the structure, function, and regulation of the molecular machines involved in each step of DNA replication.

      PubDate: 2017-05-02T09:29:20Z
      DOI: 10.1016/j.mrfmmm.2017.04.002
    • Abstract: Publication date: March 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volumes 797–799

      PubDate: 2017-05-02T09:29:20Z
  • Torsional stress promotes trinucleotidic expansion in spermatids
    • Authors: Olivier Simard; Seyedeh Raheleh Niavarani; Virginie Gaudreault; Guylain Boissonneault
      Abstract: Publication date: Available online 9 April 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Olivier Simard, Seyedeh Raheleh Niavarani, Virginie Gaudreault, Guylain Boissonneault
      Trinucleotide repeats are involved in various neurodegenerative diseases and are highly unstable both in dividing or non-dividing cells. In Huntington disease (HD), the age of onset of symptoms is inversely correlated to the number of CAG repeats within exon 1 of the HTT gene. HD shows paternal anticipation as CAG repeats are increased during spermatogenesis. CAG expansion were indeed found to be generated during the chromatin remodeling in spermatids where most histones are evicted and replaced by protamines. This process involves striking change in DNA topology since free supercoils must be eliminated. Using an in vitro CAG repeat reporter assay and a highly active nuclear extracts from spermatids, we demonstrate that free negative supercoils result in CAG TNR expansion at a stabilized hairpin. We also suggest a possible role for protamines in promoting localized torsional stress and consequently TNR expansion. The transient increase in torsional stress during spermiogenesis may therefore provide an ideal context for the generation of such secondary DNA structures leading to the paternal anticipation of trinucleotidic diseases.

      PubDate: 2017-04-11T07:40:12Z
      DOI: 10.1016/j.mrfmmm.2017.04.001
  • Towards precision prevention: Technologies for identifying healthy
           individuals with high risk of disease
    • Authors: Zachary D. Nagel; Bevin P. Engelward; David J. Brenner; Thomas J. Begley; Robert W. Sobol; Jason H. Bielas; Peter J. Stambrook; Qingyi Wei; Jennifer J. Hu; Mary Beth Terry; Caroline Dilworth; Kimberly A. McAllister; Les Reinlib; Leroy Worth; Daniel T. Shaughnessy
      Abstract: Publication date: Available online 6 April 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Zachary D. Nagel, Bevin P. Engelward, David J. Brenner, Thomas J. Begley, Robert W. Sobol, Jason H. Bielas, Peter J. Stambrook, Qingyi Wei, Jennifer J. Hu, Mary Beth Terry, Caroline Dilworth, Kimberly A. McAllister, Les Reinlib, Leroy Worth, Daniel T. Shaughnessy
      The rise of advanced technologies for characterizing human populations at the molecular level, from sequence to function, is shifting disease prevention paradigms toward personalized strategies. Because minimization of adverse outcomes is a key driver for treatment decisions for diseased populations, developing personalized therapy strategies represents an important dimension of both precision medicine and personalized prevention. In this commentary, we highlight recently developed enabling technologies in the field of DNA damage, DNA repair, and mutagenesis. We propose that omics approaches and functional assays can be integrated into population studies that fuse basic, translational and clinical research with commercial expertise in order to accelerate personalized prevention and treatment of cancer and other diseases linked to aberrant responses to DNA damage. This collaborative approach is generally applicable to efforts to develop data-driven, individualized prevention and treatment strategies for other diseases. We also recommend strategies for maximizing the use of biological samples for epidemiological studies, and for applying emerging technologies to clinical applications.
      Graphical abstract image

      PubDate: 2017-04-11T07:40:12Z
      DOI: 10.1016/j.mrfmmm.2017.03.007
  • Biotesting of water of Lake Sevan with Tradescantia (clone 02)
    • Authors: R.E. Avalyan; E.A. Aghajanyan; A. Khosrovyan; A.L. Atoyants; A.E. Simonyan; R.M. Aroutiounian
      Abstract: Publication date: Available online 31 March 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): R.E. Avalyan, E.A. Aghajanyan, A. Khosrovyan, A.L. Atoyants, A.E. Simonyan, R.M. Aroutiounian
      For many decades water resources in Armenia have been affected by anthropogenic activity, consequently, a regular bioindication of genotoxic effects of the water bodies is desirable. The genotoxicity of water samples collected from different parts of Lake Sevan were assessed by means of Trad-SHM (stamen hair mutation) assay using Tradescantia (clone 02). Here we report a significant increase in the frequency of somatic mutations and morphological changes in the Tradescantia inflorescences exposed to the water samples compared to the control. The somatic mutations (recessive mutation and white mutation events) were mostly linked to the concentration of Al, Ni, As, Co and Pb in Artanish, Tsapatakh and Karchaghbyur, Noradus, Martuni and Litchk, while morphological changes (non-surviving hairs) were related to Co level in Tsapatakh and Karchaghbyur. The results obtained show that Lake Sevan contains substances which may cause genotoxicity and teratogenicity in Tradescantia and probably also in aquatic animals. The results also show that Trad-SHM assay can be used for monitoring natural resources.

      PubDate: 2017-04-04T07:07:06Z
      DOI: 10.1016/j.mrfmmm.2017.03.006
  • The Legacy of William Morgan: The PNNL Years
    • Authors: Antone L. Brooks
      Abstract: Publication date: Available online 18 March 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Antone L. Brooks

      PubDate: 2017-03-21T06:13:29Z
      DOI: 10.1016/j.mrfmmm.2017.03.002
  • Transmission of persistent ionizing radiation-induced foci through cell
           division in human primary cells
    • Authors: Aurelie Vaurijoux; Pascale Voisin; Amelie Freneau; Joan Francesc Barquinero; Gaetan Gruel
      Abstract: Publication date: Available online 10 March 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Aurelie Vaurijoux, Pascale Voisin, Amelie Freneau, Joan Francesc Barquinero, Gaetan Gruel
      Unrepaired DNA double-strand breaks (DSBs) induced by ionizing radiation are associated with lethal effects and genomic instability. After the initial breaks and chromatin destabilization, a set of post-translational modifications of histones occurs, including phosphorylation of serine 139 of histone H2AX (γH2AX), which leads to the formation of ionizing radiation-induced foci (IRIF). DSB repair results in the disappearance of most IRIF within hours after exposure, although some remain 24hours after irradiation. Their relation to unrepaired DSBs is generally accepted but still controversial. This study evaluates the frequency and kinetics of persistent IRIF and analyzes their impact on cell proliferation. We observed persistent IRIF up to 7 days postirradiation, and more than 70% of cells exposed to 5Gy had at least one of these persistent IRIF 24hours after exposure. Moreover we demonstrated that persistent IRIF did not block cell proliferation definitively. The frequency of IRIF was lower in daughter cells, due to asymmetric distribution of IRIF between some of them. We report a positive association between the presence of IRIF and the likelihood of DNA missegregation. Hence, the structure formed after the passage of a persistent IRI focus across the S and G2 phases may impede the correct segregation of the affected chromosome's sister chromatids. The ensuing abnormal resolution of anaphase might therefore cause the nature of IRIF in daughter-cell nuclei to differ before and after the first cell division. The resulting atypical chromosomal assembly may be lethal or result in a gene dosage imbalance and possibly enhanced genomic instability, in particular in the daughter cells.

      PubDate: 2017-03-16T06:00:01Z
      DOI: 10.1016/j.mrfmmm.2017.03.003
           AND HOW
    • Authors: R. Julian Preston
      Abstract: Publication date: Available online 8 March 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): R. Julian Preston
      The process of setting radiation protection standards requires the interaction of a number of international and national organizations that in turn require the input of scientific and regulatory experts. Bill Morgan served in an expert capacity for several of these organizations particularly for the application of radiation biology data to risk assessment. He brought great enthusiasm and dedication to these committee efforts. In fact, he really enjoyed this type of service. The United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR), for example, provides comprehensive reviews of the input data for radiation risk assessments. In this context, they do not conduct risk assessments. In Europe, a research component of the risk assessment process is provided by the Multidisciplinary European Low Dose Initiative (MELODI). Specific issue areas are identified for which additional research can aid in reducing uncertainty in risk assessments. The International Commission for Radiological Protection (ICRP) uses these types of input data to develop nominal cancer risk estimates as input data for establishing dose limits for the public and workers. A similar regulatory role is provided in the US by the National Council on Radiation Protection and Measurements (NCRP). The NCRP Reports address the underlying principles for setting regulatory dose limits for the US public and workers; these differ to a limited extent from those of ICRP. The implementation of dose limits is conducted by individual countries but with significant guidance by the International Atomic Energy Agency (IAEA) through its Basic Safety Standards. The role of other national and international organizations are discussed in this same framework.

      PubDate: 2017-03-09T11:12:14Z
      DOI: 10.1016/j.mrfmmm.2017.03.004
  • Mitochondrial DNA damage and oxidative damage in HL-60 cells exposed to
           900MHz radiofrequency fields
    • Authors: Yulong Sun; Lin Zong; Zhen Gao; Shunxing Zhu; Jian Tong; Yi Cao
      Abstract: Publication date: Available online 7 March 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Yulong Sun, Lin Zong, Zhen Gao, Shunxing Zhu, Jian Tong, Yi Cao
      HL-60 cells, derived from human promyelocytic leukemia, were exposed to continuous wave 900MHz radiofrequency fields (RF) at 120μW/cm2 power intensity for 4hours/day for 5 consecutive days to examine whether such exposure is capable damaging the mitochondrial DNA (mtDNA) mediated through the production of reactive oxygen species (ROS). In addition, the effect of RF exposure was examined on 8-hydroxy-2’-dexoyguanosine (8-OHdG) which is a biomarker for oxidative damage and on the mitochondrial synthesis of adenosine triphosphate (ATP) which is the energy required for cellular functions. The results indicated a significant increase in ROS and significant decreases in mitochondrial transcription factor A, mtDNA polymerase gamma, mtDNA transcripts and mtDNA copy number in RF-exposed cells compared with those in sham-exposed control cells. In addition, there was a significant increase in 8-OHdG and a significant decrease in ATP in RF-exposed cells. The response in positive control cells exposed to gamma radiation (GR, which is also known to induce ROS) was similar to those in RF-exposed cells. Thus, the overall data indicated that RF exposure was capable of inducing mtDNA damage mediated through ROS pathway which also induced oxidative damage. Prior-treatment of RF- and GR-exposed the cells with melatonin, a well-known free radical scavenger, reversed the effects observed in RF-exposed cells.

      PubDate: 2017-03-09T11:12:14Z
      DOI: 10.1016/j.mrfmmm.2017.03.001
    • Abstract: Publication date: February 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 796

      PubDate: 2017-03-09T11:12:14Z
  • Targeted Cytoplasmic Irradiation and Autophagy
    • Authors: Jinhua Wu; Bo Zhang; Yen-Ruh Wuu; Mercy M. Davidson; Tom K. Hei
      Abstract: Publication date: Available online 1 March 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Jinhua Wu, Bo Zhang, Yen-Ruh Wuu, Mercy M. Davidson, Tom K. Hei
      The effect of ionizing irradiation on cytoplasmic organelles is often underestimated because the general dogma considers direct DNA damage in the nuclei to be the primary cause of radiation induced toxicity. Using a precision microbeam irradiator, we examined the changes in mitochondrial dynamics and functions triggered by targeted cytoplasmic irradiation with α-particles. Mitochondrial dysfunction induced by targeted cytoplasmic irradiation led to activation of autophagy, which degraded dysfunctional mitochondria in order to maintain cellular energy homeostasis. The activation of autophagy was cytoplasmic irradiation-specific and was not detected in nuclear irradiated cells. This autophagic process was oxyradical-dependent and required the activity of the mitochondrial fission protein dynamin related protein 1 (DRP1). The resultant mitochondrial fission induced phosphorylation of AMP activated protein kinase (AMPK) which leads to further activation of the extracellular signal-related kinase (ERK) 1/2 with concomitant inhibition of the mammalian target of rapamycin (mTOR) to initiate autophagy. Inhibition of autophagy resulted in delayed DNA damage repair and decreased cell viability, which supports the cytoprotective function of autophagy. Our results reveal a novel mechanism in which dysfunctional mitochondria are degraded by autophagy in an attempt to protect cells from toxic effects of targeted cytoplasmic radiation.

      PubDate: 2017-03-03T14:04:54Z
      DOI: 10.1016/j.mrfmmm.2017.02.004
  • Analysis of Microsatellite Instability in CRISPR/Cas9 Editing Mice
    • Authors: Xueyun Huo; Yating Du; Jing Lu; Meng Guo; Zhenkun Li; Shuangyue Zhang; Xiaohong Li; Zhenwen Chen; Xiaoyan Du
      Abstract: Publication date: Available online 28 February 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Xueyun Huo, Yating Du, Jing Lu, Meng Guo, Zhenkun Li, Shuangyue Zhang, Xiaohong Li, Zhenwen Chen, Xiaoyan Du
      Clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR- associated (Cas) protein 9 system is a novel and powerful tool which is widely used for genome editing. CRISPR/Cas9 is RNA-guided and can lead to desired genomic modifications. However, whether the CRISPR/Cas9-mediated genome editing causes genomic alterations and genomic instability, such as microsatellite instability (MSI), is still unknown. Here we detected MSI in 21 CRISPR/Cas9 mouse strains using a panel of 42 microsatellite loci which were selected from our previous studies. Surprisingly, MSI occurrence was common in CRISPR/Cas9 modified genome, and most of the strains (19/21, 90.5%) examined showed MSI. Of 42 loci examined, 8 loci (8/42, 19.05%) exhibited MSI in the Cas9 editing mice. The Ttll9 (4/42, 9.5%) were the most unstable strains, and D10Mit3 and D10Mit198 (9/21, 42.9%) was considered to be the most “hot” locus in the Cas9 strains we tested. Through analyzing the mutation of microsatellite loci, we provide new insights into the genomic alterations of CRISPR/Cas9 models and it will help us for a better understanding of this powerful technology.

      PubDate: 2017-03-03T14:04:54Z
      DOI: 10.1016/j.mrfmmm.2017.02.003
  • Induction of the Long Noncoding RNA NBR2 from the Bidirectional BRCA1
           Promoter Under Hypoxic Conditions
    • Authors: J. Erin Wiedmeier; Anna Ohlrich; Adrian Chu; Michael R. Rountree; Mitchell S. Turker
      Abstract: Publication date: Available online 16 February 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): J. Erin Wiedmeier, Anna Ohlrich, Adrian Chu, Michael R. Rountree, Mitchell S. Turker
      BRCA1 plays an important role in preventing breast cancer and is often silenced or repressed in sporadic cancer. The BRCA1 promoter is bidirectional: it drives transcription of the long non-coding (lnc) NBR2 transcript in the opposite orientation relative to the BRCA1 transcript. Hypoxic conditions repress BRCA1 transcription, but their effect on expression of the NBR2 transcript has not been reported. We used quantitative RT-PCR to measure BRCA1 and NBR2 transcript levels in 0% and 1% oxygen in MCF-7 breast cancer cells and found that NBR2 transcript levels increased as a function of time under hypoxic conditions, whereas BRCA1 mRNA levels were repressed. Hypoxic conditions were ineffective in reducing BRCA1 mRNA in UACC-3199 breast cancer cell line, which is reported to have an epigenetically silenced BRCA1 promoter, even though appreciable level of BRCA1 and NBR2 mRNA were detected. Significant recovery back to baseline RNA levels occurred within 48hours after the MCF-7 cells were restored to normoxic conditions. We used a construct with the 218bp minimal BRCA1 promoter linked to marker genes to show that this minimal promoter repressed expression bidirectionally under hypoxic conditions, which suggests that the elements necessary for induction of NBR2 are located elsewhere.

      PubDate: 2017-02-16T12:59:25Z
      DOI: 10.1016/j.mrfmmm.2017.02.001
  • Modulation of Modeled Microgravity on Radiation-Induced Adaptive Response
           of Root Growth in Arabidopsis thaliana
    • Authors: Chenguang Deng; Ting Wang; Jingjing Wu; Wei Xu; Huasheng Li; Min Liu; Lijun Wu; Jinying Lu; Po Bian
      Abstract: Publication date: Available online 14 February 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Chenguang Deng, Ting Wang, Jingjing Wu, Wei Xu, Huasheng Li, Min Liu, Lijun Wu, Jinying Lu, Po Bian
      Space particles have an inevitable impact on organisms during space missions; radio-adaptive response (RAR) is a critical radiation effect due to both low-dose background and sudden high-dose radiation exposure during solar storms. Although it is relevant to consider RAR within the context of microgravity, another major space environmental factor, to our knowledge, there is no evidence yet as to its effects on RAR. In the present study, we established an experimental method for detecting the effects of gamma-irradiation on the primary root growth of Arabidopsis thaliana, in which RAR of root growth was significantly induced by several dose combinations. Microgravity was simulated using a two-dimensional rotation clinostat. It was shown that RAR of root growth was significantly inhibited under the modeled microgravity condition, and was absent in pgm-1 plants that had impaired gravity sensing in root tips. These results suggest that RAR could be modulated in microgravity. Time course analysis showed that microgravity affected either the development of radio-resistance induced by priming irradiation, or the responses of plants to challenging irradiation. Consistently, priming irradiation-induced expressions of DNA repair genes (AtKu70 and AtRAD54) were attenuated in microgravity, and reduced DNA repair efficiency in response to challenging irradiation was also observed after treatment with the modeled microgravity. In plant roots, the polar transportation of phytohormone auxin is regulated by gravity, and treatment with an exogenous auxin (indole-3-acetic acid) prevented the induction of RAR of root growth, suggesting that auxin might play a regulatory role in the interaction between microgravity and RAR of root growth.

      PubDate: 2017-02-16T12:59:25Z
      DOI: 10.1016/j.mrfmmm.2017.02.002
    • Abstract: Publication date: January 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, Volume 795

      PubDate: 2017-02-05T12:26:23Z
  • The DNA damage response of C. elegans affected by gravity sensing and
           radiosensitivity during the Shenzhou-8 spaceflight
    • Authors: Ying Gao; Dan Xu; Lei Zhao; Yeqing Sun
      Abstract: Publication date: Available online 7 January 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Ying Gao, Dan Xu, Lei Zhao, Yeqing Sun
      Space radiation and microgravity are recognized as primary and inevitable risk factors for humans traveling in space, but the reports regarding their synergistic effects remain inconclusive and vary across studies due to differences in the environmental conditions and intrinsic biological sensitivity. Thus, we studied the synergistic effects on transcriptional changes in the global genome and DNA damage response (DDR) by using dys-1 mutant and ced-1 mutant of C. elegans, which respectively presented microgravity-insensitivity and radiosensitivity when exposure to spaceflight condition (SF) and space radiation (SR). The dys-1 mutation induced similar transcriptional changes under both conditions, including the transcriptional distribution and function of altered genes. The majority of alterations were related to metabolic shift under both conditions, including transmembrane transport, lipid metabolic processes and proteolysis. Under SF and SR conditions, 12/14 and 10/13 altered pathways, respectively, were both grouped in the metabolism category. Out of the 778 genes involved in DDR, except eya-1 and ceh-34, 28 altered genes in dys-1 mutant showed no predicted protein interactions, or anti-correlated miRNAs during spaceflight. The ced-1 mutation induced similar changes under SF and SR; however, these effects were stronger than those of the dys-1 mutant. The additional genes identified were related to phosphorous/phosphate metabolic processes and growth rather than, metabolism, especially for environmental information processing under SR. Although the DDR profiles were significantly changed under both conditions, the ced-1 mutation favored DNA repair under SF and apoptosis under SR. Notably, 37 miRNAs were predicted to be involved in the DDR. Our study indicates that, the dys-1 mutation reduced the transcriptional response to SF, and the ced-1 mutation increased the response to SR, when compared with the wild type C. elegans. Although some effects were due to radiosensitivity, microgravity, depending on the dystrophin, exerts predominant effects on transcription in C. elegans during short-duration spaceflight.

      PubDate: 2017-01-08T18:38:51Z
      DOI: 10.1016/j.mrfmmm.2017.01.001
  • Synergism of dam, MutH, and MutS in methylation-directed mismatch repair
           in Escherichia coli
    • Authors: Changkun Hu; Yunqi Zhao; Huiyun Sun; Yixin Yang
      Abstract: Publication date: Available online 6 January 2017
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Changkun Hu, Yunqi Zhao, Huiyun Sun, Yixin Yang
      DNA mismatch repair (MMR) is a critical mutation surveillance system for recognizing and repairing erroneous insertion, deletion, and disincorporation of base. Major components of mismatch repair system consist of MutH, MutL, and MutS. Dam methylates adenine to distinguish newly synthesized daughter strands from the parent strands. Employing a tyrosine-auxotrophic E. coli FX-11 strain, the mutation frequency can be determined by the number of tyrosine revertants and the cell viability of FX-11 with deficiencies in dam and mismatch repair proteins. This study showed that mutS defect produced a higher mutation frequency than mutH did. Interestingly, double defects in dam and mutS synergistically produced a dramatically higher spontaneous mutation frequency than the summation of mutation frequencies of FX-11 strains with individual deficiency of dam or mutS, suggesting that Dam may work with MutHL to partially accomplish the task of recognizing the mismatch sites to retain partial mismatch repair capacity.

      PubDate: 2017-01-08T18:38:51Z
      DOI: 10.1016/j.mrfmmm.2016.12.002
  • Sample size determination for the fluctuation experiment
    • Authors: Zheng
      Abstract: Publication date: Available online 19 December 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Qi Zheng
      The Luria-Delbrück fluctuation experiment protocol is increasingly employed to determine microbial mutation rates in the laboratory. An important question raised at the planning stage is “How many cultures are needed'” For over 70 years sample sizes have been determined either by intuition or by following published examples where sample sizes were chosen intuitively. This paper proposes a practical method for determining the sample size. The proposed method relies on existing algorithms for computing the expected Fisher information under two commonly used mutant distributions. The role of partial plating in reducing sample size is discussed.

      PubDate: 2016-12-22T17:47:45Z
  • Influence of reduced glutathione on end-joining of DNA double-strand
           breaks: Cytogenetical and molecular approach
    • Authors: Nitin Ghoshal; Sheetal Sharma; Atanu Banerjee; Sillarine Kurkalang; Sathees C Raghavan; Anupam Chatterjee
      Abstract: Publication date: Available online 9 November 2016
      Source:Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis
      Author(s): Nitin Ghoshal, Sheetal Sharma, Atanu Banerjee, Sillarine Kurkalang, Sathees C Raghavan, Anupam Chatterjee
      Radiation induced DNA double-strand breaks (DSB) are the major initial lesions whose misrejoining may lead to exchange aberrations. However, the role of glutathione (GSH), a major cellular thiol, in regulating cell’s sensitivity to DNA damaging agents is not well understood. Influence of endogenous GSH on the efficiency of X-rays and bleomycin (Blem) induced DNA DSBs end-joining has been tested here cytogenetically, in human lymphocytes and Hct116 cells. In another approach, oligomeric DNA (75bp) containing 5′-compatible and non-compatible overhangs mimicking the endogenous DSB were for rejoining in presence of cell-free extracts from cells having different endogenous GSH levels. Frequency of aberrations, particularly exchange aberrations, was significantly increased when Blem was combined with radiation. The exchange aberration frequency was further enhanced when combined treatment was given at 4°C since DNA lesions are poorly repaired at 4°C so that a higher number of DNA breaks persist and interact when shifted from 4°C to 37°C. The exchange aberrations increased further when the combined treatment was given to Glutathione-ester (GE) pre-treated cells, indicating more frequent rejoining of DNA lesions in presence of higher cellular GSH. This is further supported by the drastic reduction in frequency of exchange aberrations but significant increase in incidences of deletions when combined treatment was given to GSH-depleted cells. End-joining efficiency of DNA DSBs with compatible ends was better than for non-compatible ends. End-joining efficiency of testicular and MCF7 cell extracts was better than that of lungs and Hct116 cells. Cell extract made from GE-treated MCF-7 cells provided more efficient end-joining than from untreated and GSH-depleted cells. However, direct addition of GSH to the cell-free extracts showed considerable reduction in end-joining efficiency. Present data indicate that higher endogenous GSH favours rejoining of DNA DSBs (both restitution and illegitimate reunion) which in turn produce more exchange aberrations.

      PubDate: 2016-11-10T11:15:49Z
      DOI: 10.1016/j.mrfmmm.2016.10.005
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