Regulation of mammalian horizontal gene transfer by apoptotic DNA fragmentation

Yan, Biao; Wang, H; F, Li; Cy, Li

doi:10.1038/sj.bjc.6603484

Cited by 25 publications

(17 citation statements)

References 18 publications

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“…ICAD expression and mutations were recently linked to some human cancers and to an animal model of skin cancer [20], [21], [32], [40], [41]. Along with these reports, our study strengthens the notion that DFF is an important factor in tissue homeostasis by participating in the maintenance of genomic stability.…”

Section: Discussionsupporting

confidence: 87%

ICAD Deficiency in Human Colon Cancer and Predisposition to Colon Tumorigenesis: Linkage to Apoptosis Resistance and Genomic Instability

et al. 2013

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We previously showed that DNA fragmentation factor, which comprises a caspase-3-activated DNase (CAD) and its inhibitor (ICAD), may influence the rate of cell death by generating PARP-1-activating DNA breaks. Here we tested the hypothesis that ICAD-deficient colon epithelial cells exhibiting resistance to death stimuli may accumulate additional genetic modifications, leading to a tumorigenic phenotype. We show that ICAD deficiency may be associated with colon malignancy in humans. Indeed, an examination of ICAD expression using immunohistochemistry in an array of both colon cancer and normal tissues revealed that ICAD expression levels were severely compromised in the cancerous tissues. Upon DNA damage caused by a low dose of irradiation, ICAD cells acquire a tumorigenic phenotype. Colon epithelial cells derived from ICAD mice showed a significant resistance to death induced by the colon carcinogen dimethylhydrazine in vitro and in mice. Such resistance was associated with a decrease in PARP-1 activation. In an animal model of dimethylhydrazine-induced colon tumorigenesis, ICAD−/− mice developed significantly higher numbers of tumors with markedly larger sizes than the wild-type counterparts. Interestingly, the phenotype of the ICAD−/− mice was not associated with a significant increase in the precancerous aberrant crypt foci suggesting a potential link to tumor progression rather than initiation. More importantly, ICAD deficiency was associated with severe genomic instability as assessed by array comparative genomic hybridization. Such genomic instability consisted most prominently of amplifications but with sizable deletions as compared to the wild-type counterparts affecting several cancer-related genes including RAF-1, GSN, LMO3, and Fzd6 independently of p53. Altogether, our results present a viable case for the involvement of ICAD deficiency in colon carcinogenesis and show that apoptosis and genomic instability may comprise the means by which such deficiency may contribute to the process of increasing susceptibility to carcinogen-induced tumorigenesis.

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Section: Discussionsupporting

confidence: 87%

ICAD Deficiency in Human Colon Cancer and Predisposition to Colon Tumorigenesis: Linkage to Apoptosis Resistance and Genomic Instability

et al. 2013

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“…Surprisingly, significant horizontal gene transfer occurs in DNase II null recipient cells even when the p53 pathway is functional. Furthermore, the frequency of horizontal gene transfer to p53 null recipient cells is reduced some 4-to 6-fold when DFF activation is inhibited in apoptotic donor cells [110].…”

Section: Dff In Horizontal Gene Transfermentioning

confidence: 99%

“…Several investigations have shown that this can occur when donor cell apoptotic bodies are engulfed by phagocytic recipient cells [108][109][110]. The process can have important consequences because dying tumor cells can transfer their oncogenes to recipient cells and lead to the spreading of malignant transformation [109,111].…”

Section: Dff In Horizontal Gene Transfermentioning

confidence: 99%

Roles of the Major Apoptotic Nuclease-DNA Fragmentation Factor-in Biology and Disease

Widłak

Garrard

2008

Cell. Mol. Life Sci.

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It has now been more than ten years since the discovery of the major apoptotic nuclease, DNA fragmentation factor (DFF), also known as caspase-activated DNase (CAD). Here we review the recent literature that has uncovered new insight into DFF's regulation, and both its positive and negative roles in human disease. Cells from mice deficient in DFF still undergo apoptotic death without significant cell-autonomous DNA degradation. Their corpses' genomes are subsequently degraded by lysosomal DNase II after phagocytosis. However,DFF-deficient mice are more susceptible to cancer. Indeed, several different cancers in humans are associated with defects in DFF expression and it has been proposed that DFF is a p53-independent tumor suppressor. Negative aspects of DFF expression include contributing to susceptibility to acquire systemic lupus erythematosus, to chromosomal translocations that result in mixed lineage leukemias, and in the possible spreading of oncogenes and HIV due to horizontal gene transfer.

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“…This process can be remarkably efficient [28], requires CAD [29], and may induce tumor formation in vivo , possibly through the induction of gene translocations [30]. The tumor suppressor gene p53 prevents cells from replicating the transferred DNA, providing a possible explanation for the ability of cells carrying a mutant p53 gene to acquire genetic alterations [15].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2011

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DNA fragmentation is a well-recognized hallmark of apoptosis. However, the precise DNA sequences cleaved during apoptosis triggered by distinct mechanisms remain unclear. We used next-generation sequencing of DNA fragments generated in Actinomycin D-treated human HL-60 leukemic cells to generate a high-throughput, global map of apoptotic DNA breakpoints. These data highlighted that DNA breaks are non-random and show a significant association with active genes and open chromatin regions. We noted that transcription factor binding sites were also enriched within a fraction of the apoptotic breakpoints. Interestingly, extensive apoptotic cleavage was noted within genes that are frequently translocated in human cancers. We speculate that the non-random fragmentation of DNA during apoptosis may contribute to gene translocations and the development of human cancers.

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Regulation of mammalian horizontal gene transfer by apoptotic DNA fragmentation

Cited by 25 publications

References 18 publications

ICAD Deficiency in Human Colon Cancer and Predisposition to Colon Tumorigenesis: Linkage to Apoptosis Resistance and Genomic Instability

ICAD Deficiency in Human Colon Cancer and Predisposition to Colon Tumorigenesis: Linkage to Apoptosis Resistance and Genomic Instability

Roles of the Major Apoptotic Nuclease-DNA Fragmentation Factor-in Biology and Disease

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

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