دورية أكاديمية
Live-Cell Imaging Shows Uneven Segregation of Extrachromosomal DNA Elements and Transcriptionally Active Extrachromosomal DNA Hubs in Cancer.
| العنوان: | Live-Cell Imaging Shows Uneven Segregation of Extrachromosomal DNA Elements and Transcriptionally Active Extrachromosomal DNA Hubs in Cancer. |
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| المؤلفون: | Yi E; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut., Gujar AD; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut., Guthrie M; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut., Kim H; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.; Department of Biopharmaceutical Convergence, Department of Pharmacy, Sungkyunkwan University, Suwon-si, Gyeong gi-do, Korea., Zhao D; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut., Johnson KC; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut., Amin SB; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut., Costa ML; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut., Yu Q; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut., Das S; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for SickKids, University of Toronto, Toronto, Canada.; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.; Division of Neurosurgery, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Canada., Jillette N; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut., Clow PA; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut., Cheng AW; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut. roel.verhaak@jax.org albert.cheng@jax.org.; Department of Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, Connecticut.; Institute for Systems Genomics, University of Connecticut Health Center, Farmington, Connecticut., Verhaak RGW; The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut. roel.verhaak@jax.org albert.cheng@jax.org.; Department of Neurosurgery, Amsterdam UMC, Amsterdam, the Netherlands. |
| المصدر: | Cancer discovery [Cancer Discov] 2022 Feb; Vol. 12 (2), pp. 468-483. Date of Electronic Publication: 2021 Nov 24. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101561693 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2159-8290 (Electronic) Linking ISSN: 21598274 NLM ISO Abbreviation: Cancer Discov Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research |
| مواضيع طبية MeSH: | Extrachromosomal Inheritance* , Gene Amplification* , Tumor Microenvironment*, DNA/*genetics , Neoplasms/*genetics, Humans |
| مستخلص: | Oncogenic extrachromosomal DNA elements (ecDNA) play an important role in tumor evolution, but our understanding of ecDNA biology is limited. We determined the distribution of single-cell ecDNA copy number across patient tissues and cell line models and observed how cell-to-cell ecDNA frequency varies greatly. The exceptional intratumoral heterogeneity of ecDNA suggested ecDNA-specific replication and propagation mechanisms. To evaluate the transfer of ecDNA genetic material from parental to offspring cells during mitosis, we established the CRISPR-based ecTag method. ecTag leverages ecDNA-specific breakpoint sequences to tag ecDNA with fluorescent markers in living cells. Applying ecTag during mitosis revealed disjointed ecDNA inheritance patterns, enabling rapid ecDNA accumulation in individual cells. After mitosis, ecDNAs clustered into ecDNA hubs, and ecDNA hubs colocalized with RNA polymerase II, promoting transcription of cargo oncogenes. Our observations provide direct evidence for uneven segregation of ecDNA and shed new light on mechanisms through which ecDNAs contribute to oncogenesis. SIGNIFICANCE: ecDNAs are vehicles for oncogene amplification. The circular nature of ecDNA affords unique properties, such as mobility and ecDNA-specific replication and segregation behavior. We uncovered fundamental ecDNA properties by tracking ecDNAs in live cells, highlighting uneven and random segregation and ecDNA hubs that drive cargo gene transcription. See related commentary by Henssen, p. 293 . This article is highlighted in the In This Issue feature, p. 275 . (©2021 American Association for Cancer Research.) |
| التعليقات: | Comment in: Mol Cell. 2022 Feb 3;82(3):500-502. doi: 10.1016/j.molcel.2022.01.003. (PMID: 35120647) Comment in: Cancer Discov. 2022 Feb;12(2):293-295. doi: 10.1158/2159-8290.CD-21-1525. (PMID: 35140176) |
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| معلومات مُعتمدة: | R21 NS114873 United States NS NINDS NIH HHS; P30 CA034196 United States CA NCI NIH HHS; R33 CA236681 United States CA NCI NIH HHS; R01 CA237208 United States CA NCI NIH HHS; R01 HG009900 United States HG NHGRI NIH HHS; R21 CA256575 United States CA NCI NIH HHS |
| المشرفين على المادة: | 9007-49-2 (DNA) |
| تواريخ الأحداث: | Date Created: 20211125 Date Completed: 20220314 Latest Revision: 20240822 |
| رمز التحديث: | 20240822 |
| مُعرف محوري في PubMed: | PMC8831456 |
| DOI: | 10.1158/2159-8290.CD-21-1376 |
| PMID: | 34819316 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 2159-8290 |
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| DOI: | 10.1158/2159-8290.CD-21-1376 |