The genomic and spatial mobility of extrachromosomal DNA and its implications for cancer therapy

Leen, Eric van; Brückner, Lotte; Henssen, Anton

doi:10.1038/s41588-021-01000-z

Cited by 38 publications

(32 citation statements)

References 72 publications

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“…While evolution of chromothriptic ecDNA involves a single catastrophic event, we infer that the molecular evolution of circacatena occurs sequentially in an orderly way, frequently involving recombination causing serial deletions and insertions. This difference may be due to tethering of HPV-containing ecDNA to mitotic chromosomes, whereas other ecDNAs are subject to mitotic micronuclear expulsion (42). We note virus-host concatemers are inserted at intrachromosomal loci bearing sequence homology to the host DNA segments captured by virus genomes, implying that homologous recombination mediates integration.…”

Section: Discussionmentioning

confidence: 99%

Intratumoral heterogeneity and clonal evolution induced by HPV integration

Akagi

Symer

Mahmoud

et al. 2022

Preprint

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The human papillomavirus (HPV) genome is integrated into host DNA in most HPV-positive cancers, but the consequences for chromosomal integrity are unknown. Continuous long-read sequencing of oropharyngeal cancers and cancer cell lines revealed interrelated but heterogeneous genomic structures comprising repetitive patterns of concatemerized virus and host segments. Evidence of this novel form of structural variation -- termed "circacatena" here -- was detected in extrachromosomal and intrachromosomal DNA and at chromosomal rearrangements. Unique breakpoint sequences shared across structurally diverse virus-host concatemers facilitated stepwise reconstruction of their evolution from common molecular ancestors. This analysis revealed that concatemerized HPV genomes are unstable and, upon insertion into and excision from chromosomes, facilitate capture, rearrangement, and rolling-circle amplification of host DNA. The data indicate that circacatena is driven by the dynamic, aberrant replication and recombination of an oncogenic DNA virus, thereby extending known consequences of HPV integration to include promotion of intratumoral heterogeneity and clonal evolution.

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Section: Discussionmentioning

confidence: 99%

Intratumoral heterogeneity and clonal evolution induced by HPV integration

Akagi

Symer

Mahmoud

et al. 2022

Preprint

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“…Research interest in extrachromosomal DNA molecules, such as extrachromosomal circular DNA and cytosolic DNA, has been increasing during the last decade 1,20 . Here, we identified a new class of small cytosolic dsDNAs in human and mouse cell lines, which we propose to call scDNAs.…”

Section: Discussionmentioning

confidence: 99%

“…HEK293T-cGAS or HEK293T-Vector cells were transfected with the Flag-Beclin-1 plasmid. Forty-eight hours after plasmid transfection, cells were transfected with or without HT-DNA or scDNAs (1 μg/mL) and incubated at 37 °C for 6 h. Cells were then lysed with immunoprecipitation (IP) buffer (20…”

Section: Immunoprecipitationmentioning

confidence: 99%

Small cytosolic dsDNAs repress cGAS activation and induce autophagy

Liu

Chen

Zhao

et al. 2022

Preprint

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Cyclic GMP-AMP (cGAMP) synthase (cGAS), a major cytosolic DNA sensor, activates innate immune responses by producing cGAMP, which activates stimulator of interferon genes (STING). Cytosolic DNA induces autophagy in a cGAS-dependent manner to avoid persistent immune stimulation. Although dsDNAs < 20 bp can bind to cGAS, robust cGAS activation requires dsDNAs > 45 bp. However, whether cytosolic dsDNAs < 45 bp exist in mammalian cells remains unclear. Here, we identified a class of small cytosolic DNAs (scDNAs) of ~20-40 bp in human and mouse cell lines. scDNAs competed with herring testis DNA (HT-DNA, ~200-1500 bp) for binding to cGAS, and repressing HT-DNA-induced cGAS activation and the associated interferon β (IFNβ) production. Moreover, scDNAs promoted cGAS and Beclin-1 interaction, triggering the release of Rubicon, a negative regulator of phosphatidylinositol 3-kinase class III (PI3KC3) from the Beclin-1-PI3KC3 complex, activating PI3KC3 and inducing autophagy. DNA damage decreased and autophagy inducers increased scDNA levels. scDNA transfection or autophagy induction attenuated DNA damage-induced cGAS-STING activation and IFNβ expression. Thus, scDNAs acted as molecular brakes of cGAS activation, preventing excessive inflammatory cytokine production following DNA damage. Our findings lay foundations for understanding the physiological and pathological functions of scDNAs.

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“…Oncogene amplification is a classic form of genome alterations. Cancer cells are addicted to ecDNA because ecDNA is a carrier that maintains oncogene amplification [11,26,98]. Therefore, limiting the survival of cancer cells by eliminating ecDNA may be an effective therapeutic approach [99][100][101][102][103].…”

Section: The Role Of Ecdna In Cancer Treatmentmentioning

confidence: 99%

Pioneering insights of extrachromosomal DNA (ecDNA) generation, action and its implications for cancer therapy

Li¹,

Wang²,

Liang³

et al. 2022

Int. J. Biol. Sci.

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Extrachromosomal DNA (ecDNA) is a cancer-specific circular DNA molecule that is derived from chromosomes. In contrast with linear chromosomes, ecDNA exhibits a unique structure that can be representative of high chromosome accessibility, contributing to hyperactivated proto-oncogenes and malignant behaviours. Meanwhile, nonchromosomal inheritance and recurrent mutations of ecDNA fuel tumour heterogeneity and evolution. Recent studies have demonstrated that ecDNA drives tumorigenesis and progression and is related to poor clinical outcomes and drug resistance across widespread cancers. Although ecDNA was first observed in 1965, with technological advancements, its critical functions in tumorigenesis are currently coming forth. In this review, we summarize the current understanding of the origin, biogenesis process, discovery history, molecular mechanisms, and physiological functions of ecDNAs in cancer. Additionally, we highlight the effective research methods to study ecDNA and offer novel insights for ecDNA-directed therapies.

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The genomic and spatial mobility of extrachromosomal DNA and its implications for cancer therapy

Cited by 38 publications

References 72 publications

Intratumoral heterogeneity and clonal evolution induced by HPV integration

Intratumoral heterogeneity and clonal evolution induced by HPV integration

Small cytosolic dsDNAs repress cGAS activation and induce autophagy

Pioneering insights of extrachromosomal DNA (ecDNA) generation, action and its implications for cancer therapy

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