Mechanistic modelling of genetic and epigenetic events in radiation carcinogenesis

Andreev, S. G.; Eidelman, Yuri; Salnikov, I. V.; Ik, Khvostunov

doi:10.1093/rpd/ncl463

Cited by 9 publications

(1 citation statement)

References 17 publications

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“…However, the transformation ability of charged particles may also increase due to non-lethal aberrations, in particular, intrachromosomal rearrangements. This expectation is supported by a correlation of LET-dependence of relative biological efficiency (RBE) for cell neoplastic transformation and for intrachromosomal rearrangements [48]. If the correlation is causal, intrachromosomal aberrations can contribute to secondary cancers under irradiation of normal cells.…”

Section: Discussionmentioning

confidence: 96%

Chromosome Folding Promotes Intrachromosomal Aberrations under Radiation- and Nuclease-Induced DNA Breakage

Eidelman

Salnikov

Slanina

et al. 2021

IJMS

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The long-standing question in radiation and cancer biology is how principles of chromosome organization impact the formation of chromosomal aberrations (CAs). To address this issue, we developed a physical modeling approach and analyzed high-throughput genomic data from chromosome conformation capture (Hi-C) and translocation sequencing (HTGTS) methods. Combining modeling of chromosome structure and of chromosomal aberrations induced by ionizing radiation (IR) and nuclease we made predictions which quantitatively correlated with key experimental findings in mouse chromosomes: chromosome contact maps, high frequency of cis-translocation breakpoints far outside of the site of nuclease-induced DNA double-strand breaks (DSBs), the distinct shape of breakpoint distribution in chromosomes with different 3D organizations. These correlations support the heteropolymer globule principle of chromosome organization in G1-arrested pro-B mouse cells. The joint analysis of Hi-C, HTGTS and physical modeling data offers mechanistic insight into how chromosome structure heterogeneity, globular folding and lesion dynamics drive IR-recurrent CAs. The results provide the biophysical and computational basis for the analysis of chromosome aberration landscape under IR and nuclease-induced DSBs.

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Section: Discussionmentioning

confidence: 96%

Chromosome Folding Promotes Intrachromosomal Aberrations under Radiation- and Nuclease-Induced DNA Breakage

Eidelman

Salnikov

Slanina

et al. 2021

IJMS

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Epigenetic changes and nontargeted radiation effects—Is there a link?

Kovalchuk

Baulch

2008

Environ and Mol Mutagen

125

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It is now well accepted that the effects of ionizing radiation (IR) exposure can be noticed far beyond the borders of the directly irradiated tissue. IR can affect neighboring cells in the proximity, giving rise to a bystander effect. IR effects can also span several generations and influence the progeny of exposed parents, leading to transgeneration effects. Bystander and transgeneration IR effects are linked to the phenomenon of the IR‐induced genome instability that manifests itself as chromosome aberrations, gene mutations, late cell death, and aneuploidy. While the occurrence of the abovementioned phenomena is well documented, the exact mechanisms that lead to their development have still to be delineated. Evidence suggests that the IR‐induced genome instability, bystander, and transgeneration effects may be epigenetically mediated. The epigenetic changes encompass DNA methylation, histone modification, and RNA‐associated silencing. Recent studies demonstrated that IR exposure alters epigenetic parameters in the directly exposed tissues and in the distant bystander tissues. Transgeneration radiation effects were also proposed to be of an epigenetic nature. We will discuss the role of the epigenetic mechanisms in radiation responses, bystander effects, and transgeneration effects. Environ. Mol. Mutagen., 2008. © 2008 Wiley‐Liss, Inc.

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Epigenetic Effects of Ionizing Radiation

Kovalchuk

2013

Environmental Epigenomics in Health and Disease

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Pancreatic cancer is associated with a high mortality rate, owing to de novo and acquired drug resistance, thereby leading to highly invasive and metastatic pancreatic cancer cells. Therefore, targeting pancreatic cancer stem cells (CSCs) may be a novel therapeutic strategy for the treatment of pancreatic cancer. Here, we combined a DNA methylation inhibitor (5-aza-2'-deoxycytidine; 5-aza-dC) and ionizing radiation (IR) to improve anti-cancer effects by inhibiting growth and proliferation and promoting apoptosis of pancreatic cancer cells in vitro and in vivo. Importantly, the combinatorial effect of 5-aza-dC with IR on sphere-forming pancreatic cancer cells was preferentially targeted toward CSCs through the downregulation of regulatory factors of self-renewal and CSC surface markers. We next performed the RNA sequencing to understand the underlying cellular mechanisms of the combined treatment with IR and 5-aza-dC in pancreatic cancer cells. Global transcriptome profiling indicated that the expression of the Oct4-centered transcriptional network of genes was significantly downregulated in cells with combination treatment. Our data suggested that combination treatment with DNA methylation inhibitor and IR may be a novel therapeutic strategy for pancreatic cancer. Overall, these findings support the use of epigenetic therapy in combination with radiotherapy to improve therapeutic efficacy by targeting and eradicating pancreatic CSCs.

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Mechanistic modelling of genetic and epigenetic events in radiation carcinogenesis

Cited by 9 publications

References 17 publications

Chromosome Folding Promotes Intrachromosomal Aberrations under Radiation- and Nuclease-Induced DNA Breakage

Chromosome Folding Promotes Intrachromosomal Aberrations under Radiation- and Nuclease-Induced DNA Breakage

Epigenetic changes and nontargeted radiation effects—Is there a link?

Epigenetic Effects of Ionizing Radiation

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