DNA Double Strand Breaks and Chromosomal Aberrations

Obe, Günter; Durante, Marco

doi:10.1159/000303328

Cited by 39 publications

(15 citation statements)

References 141 publications

(43 reference statements)

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“…The ‘focal’ pattern of CIN we have identified in BRAF mut/MSS cancers may associate with ‘structural’ CIN which involves structural sub-chromosomal rearrangements including deletions, amplifications and translocations [20]. The causes of these types of structural aberrations may involve dysfunctional repair processes of double strand breaks by homologous recombination and the error prone non-homologous end joining [52]. Potentially many of the particularly complex patterns of structural aberrations may not be driver mechanisms in tumourigenesis but instead could be consequences of these disrupted DNA damage and repair processes.…”

Section: Discussionmentioning

confidence: 99%

Microsatellite Stable Colorectal Cancers Stratified by the BRAF V600E Mutation Show Distinct Patterns of Chromosomal Instability

et al. 2014

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The BRAF (V600E) mutation in colorectal cancers that are microsatellite stable (MSS) confers a poor patient prognosis, whereas BRAF mutant microsatellite-unstable (MSI) colorectal cancers have an excellent prognosis. BRAF wild type cancers are typically MSS and display chromosomal instability (CIN). CIN has not been extensively studied on a genome-wide basis in relation to BRAF mutational status in colorectal cancer. BRAF mutant/MSS (BRAFmut/MSS) cancers (n = 33) and BRAF mutant/MSI (BRAFmut/MSI) cancers (n = 30) were compared for presence of copy number aberrations (CNAs) indicative of CIN, with BRAF wild type/MSS (BRAFwt/MSS) cancers (n = 18) using Illumina CytoSNP-12 arrays. BRAFmut/MSS and BRAFwt/MSS cancers showed comparable numbers of CNAs/cancer at 32.8 and 29.8 respectively. However, there were differences in patterns of CNA length between MSS cohorts, with BRAFmut/MSS cancers having significantly greater proportions of focal CNAs compared to BRAFwt/MSS cancers (p<0.0001); whereas whole chromosomal arm CNAs were more common in BRAFwt/MSS cancers (p<0.0001). This related to a reduced average CNA length in BRAFmut/MSS compared to BRAFwt/MSS cancers (20.7 Mb vs 33.4 Mb;p<0.0001); and a smaller average percent of CIN affected genomes in BRAFmut/MSS compared to BRAFwt/MSS cancers (23.9% vs 34.9% respectively). BRAFmut/MSI cancers were confirmed to have low CNA rates (5.4/cancer) and minimal CIN-affected genomes (average of 4.5%) compared to MSS cohorts (p<0.0001). BRAFmut/MSS cancers had more frequent deletion CNAs compared to BRAFwt/MSS cancers on 6p and 17q at loci not typically correlated with colorectal cancer, and greater amplification CNAs on 8q and 18q compared to BRAFwt/MSS cancers. These results indicate that comparable rates of CIN occur between MSS subgroups, however significant differences in their patterns of instability exist, with BRAFmut/MSS cancers showing a ‘focal pattern’ and BRAFwt/MSS cancers having a ‘whole arm pattern’ of CIN. This and the genomic loci more frequently affected in BRAFmut/MSS cancers provides further evidence of the biological distinctions of this important cancer subgroup.

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Section: Discussionmentioning

confidence: 99%

Microsatellite Stable Colorectal Cancers Stratified by the BRAF V600E Mutation Show Distinct Patterns of Chromosomal Instability

et al. 2014

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“…The occurrence of spatial associations between chromatin segments were proven for centromeres, telomeres, replication origins, enhancers, promoters and chromosome break ends (Cavalli, 2007; Duan et al, 2010; Obe and Durante, 2010; Li et al, 2012; Sanyal et al, 2012; Crevillen et al, 2013; Dekker et al, 2013; Jin et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

Chromatin associations in Arabidopsis interphase nuclei

2014

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The arrangement of chromatin within interphase nuclei seems to be caused by topological constraints and related to gene expression depending on tissue and developmental stage. In yeast and animals it was found that homologous and heterologous chromatin association are required to realize faithful expression and DNA repair. To test whether such associations are present in plants we analyzed Arabidopsis thaliana interphase nuclei by FISH using probes from different chromosomes. We found that chromatin fiber movement and variable associations, although in general relatively seldom, may occur between euchromatin segments along chromosomes, sometimes even over large distances. The combination of euchromatin segments bearing high or low co-expressing genes did not reveal different association frequencies probably due to adjacent genes of deviating expression patterns. Based on previous data and on FISH analyses presented here, we conclude that the global interphase chromatin organization in A. thaliana is relatively stable, due to the location of its 10 centromeres at the nuclear periphery and of the telomeres mainly at the centrally localized nucleolus. Nevertheless, chromatin movement enables a flexible spatial genome arrangement in plant nuclei.

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“…Chromosome aberrations, especially breaks probably act at the G2 phase of the cell cycle (Biswas et al 2004). Clastogenic agents may induce DNA double-strand breaks and lead to either cell cycle arrest or apoptosis (Kastan et al 1991;Bunz et al 1998;Morrison et al 2000;Obe and Durante 2010). The results of this research showed that dioxacarb did not induce a significant increase in CAs compared to the control group and so dioxacarb was not identified as a clastogenic agent.…”

Section: Discussionmentioning

confidence: 71%

Cytotoxic and genotoxic effects of dioxacarb by human peripheral blood lymphocytes CAs and Allium test

et al. 2014

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Dioxacarb (Elecron, Famid) is a phenyl methylcarbamate insecticide and in vitro cytotoxic and genotoxic effects of this pesticide on human peripheral blood lymphocytes and Allium root meristematic cells were investigated by chromosomal aberrations (CAs) and Allium test. Human lymphocytes were treated with 62.5, 125, 250 and 500 ppm doses of dioxacarb for CAs. CA/cell, abnormal cell % and mitotic index % (MI %) data were obtained from these concentrations in 24 and 48 h treatment periods. Dioxacarb did not increase the CA/cell frequency significantly, so this insecticide was not identified as genotoxic. But it was found cytotoxic especially at 250 and 500 ppm concentrations because of the reduced the MI % and increased the abnormal cell %. In Allium test, 25 ppm (EC50/2), 50 ppm (EC50) and 100 ppm (EC50 9 2) concentrations were used for root growth inhibition (EC50 determination) and Allium mitotic index (MI) determination tests. The used concentrations of dioxacarb induced dose-dependent inhibition of MI and root growth on root meristems. Mitotic inhibition of dioxacarb was found significantly higher than for the positive control. These Allium results indicated the high cytotoxicity of dioxacarb. The present study is the first research on cytotoxicity and genotoxicity of dioxacarb by human lymphocyte CAs and Allium test.

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DNA Double Strand Breaks and Chromosomal Aberrations

Cited by 39 publications

References 141 publications

Microsatellite Stable Colorectal Cancers Stratified by the BRAF V600E Mutation Show Distinct Patterns of Chromosomal Instability

Microsatellite Stable Colorectal Cancers Stratified by the BRAF V600E Mutation Show Distinct Patterns of Chromosomal Instability

Chromatin associations in Arabidopsis interphase nuclei

Cytotoxic and genotoxic effects of dioxacarb by human peripheral blood lymphocytes CAs and Allium test

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