Next-Generation Sequencing of Apoptotic DNA Breakpoints Reveals Association with Actively Transcribed Genes and Gene Translocations

Fullwood, Melissa J.; Lee, Joanne; Lin, Lei; Li, Guoliang; Huss, Mikael; Ng, Patrick; Sung, Wing-Kin; Shenolikar, Shirish

doi:10.1371/journal.pone.0026054

Cited by 12 publications

(9 citation statements)

References 69 publications

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“…While the mechanism(s) responsible for the generation of chromothripsis remain elusive, a number of studies have proposed hypotheses including ionizing radiation [9], DNA replication stress [45], breakage-fusion-bridge cycles [9,23,46], premature chromosome compaction [47], failed apoptosis [48,49] and micronuclei formation [50]. Some of these proposed mechanisms are associated with features which could be addressed in our study.…”

Section: Resultsmentioning

confidence: 98%

Chromothripsis-like patterns are recurring but heterogeneously distributed features in a survey of 22,347 cancer genome screens

Cai

Kumar

Bagheri

et al. 2014

Preprint

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Background: Chromothripsis is a recently discovered phenomenon of genomic rearrangement, possibly arising during a single genome-shattering event. This could provide an alternative paradigm in cancer development, replacing the gradual accumulation of genomic changes with a "one-off" catastrophic event. However, the term has been used with varying operational definitions, with the minimal consensus being a large number of locally clustered copy number aberrations. The mechanisms underlying these chromothripsis-like patterns (CTLP) and their specific impact on tumorigenesis are still poorly understood. Results: Here, we identified CTLP in 918 cancer samples, from a dataset of more than 22,000 oncogenomic arrays covering 132 cancer types. Fragmentation hotspots were found to be located on chromosome 8, 11, 12 and 17. Among the various cancer types, soft-tissue tumors exhibited particularly high CTLP frequencies. Genomic context analysis revealed that CTLP rearrangements frequently occurred in genomes that additionally harbored multiple copy number aberrations (CNAs). An investigation into the affected chromosomal regions showed a large proportion of arm-level pulverization and telomere related events, which would be compatible to a number of underlying mechanisms. We also report evidence that these genomic events may be correlated with patient age, stage and survival rate.

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Section: Resultsmentioning

confidence: 98%

Chromothripsis-like patterns are recurring but heterogeneously distributed features in a survey of 22,347 cancer genome screens

Cai

Kumar

Bagheri

et al. 2014

Preprint

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“…Genome sequencing of DNA breaks caused by apoptotic nucleases, like CAD, revealed that they localized at actively transcribed genes, particularly at genes frequently translocated in human cancer. 26 The involvement of sublethal apoptotic signaling in mutagenesis induced by death receptor agonists, mitotic poisons and topoisomerase inhibitors may help define the oncogenic potential of these drugs.…”

Section: Discussionmentioning

confidence: 99%

“…Cleavage of a region of the mixed myeloid lineage (MLL) gene could be induced by drugs that target topoisomerases or (to a lesser extent) by apoptotic stimuli including death ligands. 24 , 25 , 26 , 27 The DNA-strand breaks within MLL appeared to involve error-prone repair via non-homologous end joining (NHEJ), which may contribute to the high incidence of chromosomal translocations associated with therapy-related acute myeloid leukemia. 28 CAD has been directly linked to DNA damage in various contexts.…”

mentioning

confidence: 99%

Executioner caspases and CAD are essential for mutagenesis induced by TRAIL or vincristine

Miles

Hawkins

2017

Cell Death Dis

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Chemotherapy drugs interfere with cellular processes to generate genotoxic lesions that activate cell death pathways. Sustained DNA damage induced by these drugs can provoke mutations in surviving non-cancerous cells, potentially increasing the risk of therapy-related cancers. Ligation of death receptors by ligands such as TRAIL, and subsequent activation of extrinsic apoptotic pathways, also provokes mutations. In this study, we show that executioner caspase activation of the apoptotic nuclease CAD/DFF40 is essential for TRAIL-induced mutations in surviving cells. As exposure to chemotherapy drugs also activates apoptotic caspases and presumably CAD, we hypothesized that these pathways may also contribute to the mutagenesis induced by conventional chemotherapy drugs, perhaps augmenting the mutations that arise from direct DNA damage provoked by these agents. Interestingly, vincristine-mediated mutations were caspase and CAD dependent. Executioner caspases accounted for some of the mutations caused by the topoisomerase poisons doxorubicin and SN38, but were dispensable for mutagenesis following treatment with cisplatin or temozolomide. These data highlight a non-apoptotic role of caspases in mutagenesis mediated by death receptor agonists, microtubule poisons and topoisomerase inhibitors, and provide further evidence for a potential carcinogenic consequence of sublethal apoptotic signaling stimulated by anticancer therapies.

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“…Localization of CAD‐induced DNA breaks during these nonapoptotic processes is also of considerable importance. Although apoptotic DNA breaks are largely thought to occur at random across the genome, more recent sequence‐based mapping of the breaks has indicated enrichment at specific sites . Indeed, CAD‐induced DNA breaks that appear during prolonged mitotic arrest localize to telomeric regions.…”

Section: Cad: Perspectivesmentioning

confidence: 99%

The caspase‐activated DNase: apoptosis and beyond

2016

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Organismal development and function requires multiple and accurate signal transduction pathways to ensure that proper balance between cell proliferation, differentiation, inactivation, and death is achieved. Cell death via apoptotic caspase signal transduction is extensively characterized and integral to this balance. Importantly, the view of apoptotic signal transduction has expanded over the previous decades. Subapoptotic caspase signaling has surfaced as mechanism that can promote the adoption of a range of cellular fates. An emerging mechanism of subapoptotic caspase signaling is the activation of the caspase‐activated DNase (CAD) through controlled cleavage of the inhibitor of CAD (ICAD). CAD‐induced DNA breaks incite a DNA damage response, frequently invoking p53 signaling, that transduces a change in cell fate. Cell differentiation and senescence are fates demonstrated to arise from CAD‐induced DNA breaks. Furthermore, an apparent consequence of CAD activity is also emerging, as a potential source of oncogenic mutations. This review will discuss the mechanisms underlying CAD‐induced DNA breaks and highlight how CAD activity promotes diverse cell fates.

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Next-Generation Sequencing of Apoptotic DNA Breakpoints Reveals Association with Actively Transcribed Genes and Gene Translocations

Cited by 12 publications

References 69 publications

Chromothripsis-like patterns are recurring but heterogeneously distributed features in a survey of 22,347 cancer genome screens

Chromothripsis-like patterns are recurring but heterogeneously distributed features in a survey of 22,347 cancer genome screens

Executioner caspases and CAD are essential for mutagenesis induced by TRAIL or vincristine

The caspase‐activated DNase: apoptosis and beyond

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