Classification of extrachromosomal circular DNA with a focus on the role of extrachromosomal DNA (ecDNA) in tumor heterogeneity and progression

Liao, Zhenyu; Jiang, Wang; Ye, Long‐Yun; Li, Tianjiao; Lei, Yu

doi:10.1016/j.bbcan.2020.188392

Cited by 61 publications

(62 citation statements)

References 103 publications

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“…Oncogenic mutations induce accelerated DNA replication and trigger replication stress. The so-called common fragile sites in the genome, such as rDNA, are difficult to replicate, and stalled or collapsed replication forks usually induce the formation of UFBs ultrafine bridges) or lagging chromosomes to result in MN formation or to generate free DNA fragments, such as eccrDNA, which are hard to enclose in the late phase of mitosis during nuclear membrane assembly and are consequently released to the cytoplasm ( 16 , 42 ). In our investigation, in addition to MNs, cytoplasmic DNA from the genome, including Alu-repeated sequences and rDNA, was easily detected, indicating a replication stress-related mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…MNs have been identified as the major source of cytoplasmic DNA involved in the activation of the cGAS-STING machinery to promote cancer progression and metastasis (13)(14)(15). Moreover, free DNA derived from ecc rDNA (extrachromosomal circular rDNA) could also trigger cGAS-STING activity (16). In addition, endogenous cytoplasmic DNA could be derived from mitochondria, which are injured under many circumstances (17).…”

Section: Introductionmentioning

confidence: 99%

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Autophagy-Mediated Clearance of Free Genomic DNA in the Cytoplasm Protects the Growth and Survival of Cancer Cells

Yao

Cao

et al. 2021

Front. Oncol.

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The cGAS (GMP-AMP synthase)-mediated senescence-associated secretory phenotype (SASP) and DNA-induced autophagy (DNA autophagy) have been extensively investigated in recent years. However, cGAS-mediated autophagy has not been elucidated in cancer cells. The described investigation revealed that active DNA autophagy but not SASP activity could be detected in the BT-549 breast cancer cell line with high micronucleus (MN) formation. DNA autophagy was identified as selective autophagy of free genomic DNA in the cytoplasm but not nucleophagy. The process of DNA autophagy in the cytosol could be initiate by cGAS and usually cooperates with SQSTM1-mediated autophagy of ubiquitinated histones. Cytoplasmic DNA, together with nuclear proteins such as histones, could be derived from DNA replication-induced nuclear damage and MN collapse. The inhibition of autophagy through chemical inhibitors as well as the genomic silencing of cGAS or SQSTM1 could suppress the growth and survival of cancer cells, and induced DNA damage could increase the sensitivity to these inhibitors. Furthermore, expanded observations of several other kinds of human cancer cells indicated that high relative DNA autophagy or enhancement of DNA damage could also increase or sensitize these cells to inhibition of DNA autophagy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Autophagy-Mediated Clearance of Free Genomic DNA in the Cytoplasm Protects the Growth and Survival of Cancer Cells

Yao

Cao

et al. 2021

Front. Oncol.

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“…There has always been confusion and a lack of clarity around the naming and classification of eccDNA, which has posed a problem for researchers. Since the size of eccDNA remains inconclusive and the mainstream view is that its length ranges from 10 to millions of bp (base pairs), this review classifies it into the following four categories based on size and sequence: (1) small polydispersed circular DNA (spcDNA) (100–10 kb) [ 6 , 7 ], (2) telomeric circles (t-circles) (multiples of 738 bp) [ 8 ], (3) microDNA (100–400 bp) [ 9 , 10 ], and (4) extrachromosomal DNA (ecDNA) (1–3 Mb) [ 11 ] (Table 1 [ 12 ]). Recent studies have shown that eccDNA is associated with a variety of diseases, such as ageing and cancer [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Extrachromosomal circular DNA: a new potential role in cancer progression

et al. 2021

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Extrachromosomal circular DNA (eccDNA) is considered a circular DNA molecule that exists widely in nature and is independent of conventional chromosomes. eccDNA can be divided into small polydispersed circular DNA (spcDNA), telomeric circles (t-circles), microDNA, and extrachromosomal DNA (ecDNA) according to its size and sequence. Multiple studies have shown that eccDNA is the product of genomic instability, has rich and important biological functions, and is involved in the occurrence of many diseases, including cancer. In this review, we focus on the discovery history, formation process, characteristics, and physiological functions of eccDNAs; the potential functions of various eccDNAs in human cancer; and the research methods employed to study eccDNA.

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“…Oncogenic mutations induce accelerated DNA replication and trigger replication stress. The so-called common fragile sites in the genome, such as rDNA, are di cult to replicate, and stalled or collapsed replication forks usually induce the formation of UFBs (ultra ne bridges) or lagging chromosomes to result in MN formation or to generate free DNA fragments, such as eccrDNA, which are hard to enclose in the late phase of mitosis during nuclear membrane assembly and are consequently released to the cytoplasm [16,34]. In our investigation, in addition to MNs, cytoplasmic DNA from the genome, including Alu-repeated sequences and rDNA, was easily detected, indicating a replication stressrelated mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…MNs have been identi ed as the major source of cytoplasmic DNA involved in the activation of the cGAS-STING machinery to promote cancer progression and metastasis [13][14][15]. Moreover, free DNA derived from ecc rDNA (extrachromosomal circular rDNA) could also trigger cGAS-STING activity [16]. In addition, endogenous cytoplasmic DNA could be derived from mitochondria, which are injured under many circumstances [17].…”

Section: Introductionmentioning

confidence: 99%

Autophagy-Mediated Clearance of Free Genomic DNA in the Cytoplasm Promoted the Growth and Survival of Breast Cancer Cells

Yao

Cao

et al. 2021

Preprint

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Background: The cGAS (GMP-AMP synthase)-triggered senescence-associated secretory phenotype (SASP) in promotion of cancer progression has been extensively documented. However, the role of cGAS-mediated DNA autophagy is little evaluated in breast cancer cells.Methods: Immunofluorescence, senescence associated-β-galactosidase staining (SA-β-gal) and Western blot were performed to detect gene expression, distribution and phenotypes. PCR, IP-PCR, FISH, BrdU, Comet assay, coimmunoprecipitation, sucrose density gradient centrifugation were carried out to detect possible mechanisms. Trypan blue exclusion, Live/dead staining and MTS assay were to measure the cell viability. All analyses were performed using GraphPad Prism 8. Relationships were analyzed using t-tests. A P-value of less than 0.05 was considered significant. All statistical tests and P values were 2-sided, and the level of significance was set at <0.05 (*), <0.01 (**), <0.001 (***), or<0.0001 (****); ns indicates no significance.Results: Active DNA autophagy but not SASP activity could be detected in breast cancer cells with high micronucleus (MN). The selective autophagy of free genomic DNA in the cytoplasm is mediated by cGAS and usually coordinated with SQSTM1-mediated autophagy of ubiquitinated histones in breast cancer cell lines with high frequency of MN formation. Cytoplasmic DNA together with nuclear proteins derive from DNA replication-induced nuclear damage and MN collapse in breast cell lines which with severe DNA damage. The inhibition of DNA autophagy through either chemical inhibitors or genomic silencing of cGAS or SQSTM1 suppresses the growth and survival of breast cancer cells, while enhanced DNA damage increases the sensitivity to these inhibitors for more cancer cells. Human cancer cells with either high DNA autophagy or enhancement of DNA damage are sensitive to inhibition of DNA autophagy.Conclusions: Our investigation revealed DNA autophagy in breast cancer cells with high MN formation. Autophagy of genomic DNA in the cytosol could be mediated by cGAS but is usually coordinated with other autophagic mediators. The selective autophagy mediated clearance of free genomic DNA protects of growth and survival in breast cancer cells even, and autophagic inhibition could be a potential therapeutic approach for cancer cells with high DNA autophagic activity.

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Classification of extrachromosomal circular DNA with a focus on the role of extrachromosomal DNA (ecDNA) in tumor heterogeneity and progression

Cited by 61 publications

References 103 publications

Autophagy-Mediated Clearance of Free Genomic DNA in the Cytoplasm Protects the Growth and Survival of Cancer Cells

Autophagy-Mediated Clearance of Free Genomic DNA in the Cytoplasm Protects the Growth and Survival of Cancer Cells

Extrachromosomal circular DNA: a new potential role in cancer progression

Autophagy-Mediated Clearance of Free Genomic DNA in the Cytoplasm Promoted the Growth and Survival of Breast Cancer Cells

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