Innovative insights into extrachromosomal circular DNAs in gynecologic tumors and reproduction DOI Creative Commons

Ning Wu,

Ling Wei, Zhipeng Zhu

et al.

Protein & Cell, Journal Year: 2023, Volume and Issue: 15(1), P. 6 - 20

Published: May 26, 2023

Abstract Originating but free from chromosomal DNA, extrachromosomal circular DNAs (eccDNAs) are organized in form and have long been found unicellular multicellular eukaryotes. Their biogenesis function poorly understood as they characterized by sequence homology with linear for which few detection methods available. Recent advances high-throughput sequencing technologies revealed that eccDNAs play crucial roles tumor formation, evolution, drug resistance well aging, genomic diversity, other biological processes, bringing it back to the research hotspot. Several mechanisms of eccDNA formation proposed, including breakage-fusion-bridge (BFB) translocation–deletion–amplification models. Gynecologic tumors disorders embryonic fetal development major threats human reproductive health. The these pathological processes partially elucidated since first discovery pig sperm double minutes ovarian cancer ascites. present review summarized history, biogenesis, currently available analytical clarified their functions gynecologic reproduction. We also proposed application targets liquid biopsy markers prenatal diagnosis early detection, prognosis, treatment tumors. This lays theoretical foundations future investigations into complex regulatory networks vital physiological processes.

Language: Английский

Parallel sequencing of extrachromosomal circular DNAs and transcriptomes in single cancer cells DOI Creative Commons
Rocío Chamorro González, Thomas Conrad, Maja C Stöber

et al.

Nature Genetics, Journal Year: 2023, Volume and Issue: 55(5), P. 880 - 890

Published: May 1, 2023

Abstract Extrachromosomal DNAs (ecDNAs) are common in cancer, but many questions about their origin, structural dynamics and impact on intratumor heterogeneity still unresolved. Here we describe single-cell extrachromosomal circular DNA transcriptome sequencing (scEC&T-seq), a method for parallel of full-length mRNA from single cells. By applying scEC&T-seq to cancer cells, intercellular differences ecDNA content while investigating transcriptional impact. Oncogene-containing ecDNAs were clonally present cells drove oncogene expression differences. In contrast, other small exclusive individual indicating selection propagation. Intercellular structure pointed recombination as mechanism evolution. These results demonstrate an approach systematically characterize both large which will facilitate the analysis these elements beyond.

Language: Английский

Citations

46
The two sides of chromosomal instability: drivers and brakes in cancer DOI Creative Commons
Rendy Hosea,

Sharon Hillary,

S. Hassan R. Naqvi

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: March 29, 2024

Abstract Chromosomal instability (CIN) is a hallmark of cancer and associated with tumor cell malignancy. CIN triggers chain reaction in cells leading to chromosomal abnormalities, including deviations from the normal chromosome number or structural changes chromosomes. arises errors DNA replication segregation during division, formation abnormal and/or structure Errors result licensing as well stress, such double-strand breaks stalled forks; meanwhile, stem defects machinery, centrosome amplification, erroneous microtubule–kinetochore attachments, spindle assembly checkpoint, defective sister chromatids cohesion. In cells, deleterious damage, proteotoxic metabolic alteration, cycle arrest, senescence. Paradoxically, despite these negative consequences, one hallmarks found over 90% solid tumors blood cancers. Furthermore, could endow enhanced adaptation capabilities due increased intratumor heterogeneity, thereby facilitating adaptive resistance therapies; however, excessive induce death, “just-right” model for tumors. Elucidating complex nature crucial understanding dynamics tumorigenesis developing effective anti-tumor treatments. This review provides an overview causes consequences CIN, paradox phenomenon that continues perplex researchers. Finally, this explores potential CIN-based therapy.

Language: Английский

Citations

43
Aneuploidy and complex genomic rearrangements in cancer evolution DOI
Toby M. Baker, Sara Waise, Maxime Tarabichi

et al.

Nature Cancer, Journal Year: 2024, Volume and Issue: 5(2), P. 228 - 239

Published: Jan. 29, 2024

Language: Английский

Citations

22
Chromosomal instability as a driver of cancer progression DOI

Xuelan Chen,

Albert S. Agustinus, Jun Li

et al.

Nature Reviews Genetics, Journal Year: 2024, Volume and Issue: 26(1), P. 31 - 46

Published: July 29, 2024

Language: Английский

Citations

20
Randomizing the human genome by engineering recombination between repeat elements DOI
Jonas Koeppel, Raphaël Ferreira,

Thomas Vanderstichele

et al.

Science, Journal Year: 2025, Volume and Issue: 387(6733)

Published: Jan. 30, 2025

We lack tools to edit DNA sequences at scales necessary study 99% of the human genome that is noncoding. To address this gap, we applied CRISPR prime editing insert recombination handles into repetitive sequences, up 1697 per cell line, which enables generating large-scale deletions, inversions, translocations, and circular DNA. Recombinase induction produced more than 100 stochastic megabase-sized rearrangements in each cell. tracked these over time measure selection pressures, finding a preference for shorter variants avoided essential genes. characterized 29 clones with multiple rearrangements, an impact deletions on expression genes variant but not nearby This genome-scrambling strategy large sequence relocations, insertion regulatory elements explore dispensability organization.

Language: Английский

Citations

2
Extrachromosomal circular DNA and structural variants highlight genome instability in Arabidopsis epigenetic mutants DOI Creative Commons
Panpan Zhang,

Assane Mbodj,

Abirami Soundiramourtty

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Aug. 28, 2023

Abundant extrachromosomal circular DNA (eccDNA) is associated with transposable element (TE) activity. However, how the eccDNA compartment controlled by epigenetic regulations and what its impact on genome understudied. Here, using long reads, we sequence both of Arabidopsis thaliana mutant plants affected in methylation post-transcriptional gene silencing. We detect a high load TE-derived truncated chimeric forms. On genomic side, top full length TE neo-insertions, complex structural variations (SVs) notably at disease resistance cluster being natural hotspot SV. Finally, serendipitously identify large tandem duplications hypomethylated plants, suggesting that SVs could have been overlooked mutants. propose may alter repair pathways leading to instability accumulation SVs, least plants.

Language: Английский

Citations

27
Mapping extrachromosomal DNA amplifications during cancer progression DOI Creative Commons
Hoon Kim, Soyeon Kim, Taylor Wade

et al.

Nature Genetics, Journal Year: 2024, Volume and Issue: 56(11), P. 2447 - 2454

Published: Oct. 14, 2024

To understand the role of extrachromosomal DNA (ecDNA) amplifications in cancer progression, we detected and classified focal 8,060 newly diagnosed primary cancers, untreated metastases heavily pretreated tumors. The ecDNAs were at significantly higher frequency metastatic tumors compared to cancers. Tumors from chemotherapy-pretreated patients showed ecDNA In particular, tubulin inhibition associated with increases, suggesting a for treatment response. longitudinally matched tumor samples, more likely be retained chromosomal amplifications. EcDNAs shared between time points, advanced cancers harbor localized hypermutation events private Relatively high variant allele fractions hypermutations implicated early mutagenesis. Our findings nominate provide competitive advantages during progression metastasis. A pan-cancer genomic analysis finds an increase treated primary, as well features enriched disease.

Language: Английский

Citations

10
Extrachromosomal circular DNA in colorectal cancer: biogenesis, function and potential as therapeutic target DOI Creative Commons

Yinnan Chen,

Quanpeng Qiu,

Junjun She

et al.

Oncogene, Journal Year: 2023, Volume and Issue: 42(13), P. 941 - 951

Published: March 1, 2023

Abstract Extrachromosomal circular DNA (ecDNA) has gained renewed interest since its discovery more than half a century ago, emerging as critical driver of tumor evolution. ecDNA is highly prevalent in many types cancers, including colorectal cancer (CRC), which one the most deadly cancers worldwide. ecDNAs play an essential role regulating oncogene expression, intratumor heterogeneity, and resistance to therapy independently canonical chromosomal alterations CRC. Furthermore, existence attributed patient’s prognosis, ecDNA-based amplification adversely affects clinical outcomes. Recent understanding put extra layer complexity pathogenesis In this review, we will discuss current on mechanisms biogenesis, distinctive features addition, examine how mediate overexpression, gene regulation, topological interactions with active chromatin, facilitates genetic accelerates CRC malignancy, enhances rapid adaptation resistance. Finally, potential diagnostic therapeutic implications

Language: Английский

Citations

18
3D genomic analysis reveals novel enhancer-hijacking caused by complex structural alterations that drive oncogene overexpression DOI Creative Commons
Katelyn L. Mortenson,

Courtney Dawes,

Emily R. Wilson

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: July 20, 2024

Abstract Cancer genomes are composed of many complex structural alterations on chromosomes and extrachromosomal DNA (ecDNA), making it difficult to identify non-coding enhancer regions that hijacked activate oncogene expression. Here, we describe a 3D genomics-based analysis called HAPI (Highly Active Promoter Interactions) characterize hijacking. HiChIP data from 34 cancer cell lines identified hijacking events both known potentially novel oncogenes such as MYC, CCND1 , ETV1 CRKL ID4 . Furthermore, found among multiple different chromosomes, often including MYC the same amplicons ecDNA. We characterized - ERBB2 chimeric ecDNA, in which heavily hijacks ’s enhancers. Notably, CRISPRi promoter led increased interaction with enhancers elevated Our tool provides robust strategy detect reveals insights into activation.

Language: Английский

Citations

8
Randomizing the human genome by engineering recombination between repeat elements DOI Creative Commons
Jonas Koeppel, Raphaël Ferreira,

Thomas Vanderstichele

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 23, 2024

Abstract While protein-coding genes are characterized increasingly well, 99% of the human genome is non-coding and poorly understood. This gap due to a lack tools for engineering variants that affect sequence necessary extent. To bridge this gap, we have developed toolbox create deletions, inversions, translocations, extrachromosomal circular DNA at scale by highly multiplexed insertion recombinase recognition sites into repetitive sequences with CRISPR prime editing. Using strategy, derived stable cell lines several thousand clonal insertions, highest number novel inserted single genomes. Subsequent induction generated an average more than one hundred megabase-sized rearrangements per cell, thousands across whole population. The ability detect as they track their abundance over time allowed us measure selection pressures acting on different types structural changes. We observed consolidation towards shorter preferentially delete growth-inhibiting depletion translocations. isolated 21 clones multiple recombinase-induced rearrangements. These included viable haploid deletions span hundreds kilobases well triploid HEK293T aneuploidies fold back chromosomes. mapped impact these genetic changes gene expression decipher how regulation. scrambling strategy here makes it possible megabases sequence, move between within chromosomes, implant regulatory elements new contexts which will shed light organization principles humans other species.

Language: Английский

Citations

7