Biology:Double minute

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Double minutes are small fragments of extrachromosomal DNA, which have been observed in a large number of human tumors including breast, lung, ovary, colon, and most notably, neuroblastoma. They are a manifestation of gene amplification as a result of chromothripsis,[1] during the development of tumors, which give the cells selective advantages for growth and survival. This selective advantage is as a result of double minutes frequently harboring amplified oncogenes and genes involved in drug resistance. DMs, like actual chromosomes, are composed of chromatin and replicate in the nucleus of the cell during cell division. Unlike typical chromosomes, they are composed of circular fragments of DNA, up to only a few million base pairs in size, and contain no centromere or telomere. Further to this, they often lack key regulatory elements, allowing genes to be constitutively expressed. The term ecDNA may be used to refer to DMs in a more general manner.

Formation

The most commonly proposed mechanism for DM formation is through chromothripsis, where up to hundreds of genomic arrangements occur in a single catastrophic event, and chromosome fragments which are not reintegrated join to create DMs.[1] Specific models of DM formation other than chromothripsis have also been suggested. In the “deletion-plus-episome” model, also known as the “episome model,” DNA segments are excised from an intact chromosome, circularized, then amplified as DMs by mutual recombination.[2] The “translocation-excision-deletion-amplification” model supports that during a translocation event, DMs are formed from the breakpoint region, in the process deleting the genes that are amplified from the chromosome.[3] Another suggested mechanism is a multi-step evolutionary process, shown in the GLC1 cell line, in which a series of chromosomal mutation events within amplicons create subpopulations of DMs.[4] Aside from these models, several studies suggest other processes for DM formation such as through the breakdown of a homogeneously staining region (HSR) following cell fusion,[5] through chromosomal breaks due to hypoxia induced activation of fragile sites,[6] or reduction in the level of DNA methylation.[7]

Role in Gene Amplification

DM formation is particularly important for its role in gene amplification. In addition to their ability to harbor genes, DMs are autonomously replicating, facilitating further gene amplification.[2] The circular and less compressed structure of DMs also allows for an increased transcriptional level by having a more open conformation that is more accessible to transcriptional elements and contact with enhancers.[8] The “breakage-fusion-bridge” cycle, which describes an event where telomere loss causes the repeated joining and pulling apart of sister chromatids as cell division occurs, is a popular model to explain the amplification of intrachromosomal genes. While this process does not directly produce DMs, it has been suggested as an early step in their formation, so may also contribute to gene amplification by DMs.[9]

Role in Cancer

The presence of DMs in tumor cells is a somewhat rare occurrence, but certain cancers have been found to have a high incidence rate. An extensive cancer database search found that about 1.4% of all cases are positive for DMs, and out of cancer types, neuroblastoma has the highest frequency of DMs at 31.7%.[10] The amplification of specific genes that support the growth of tumor cells, such as oncogenes or drug-resistant genes, is critical to the cell adoption of malignancy.[11] Due to their role in gene amplification, the presence of DMs can therefore be a factor in acceleration of tumor growth. One example of this is DM facilitated amplification of the MYC gene in patients with acute myeloid leukemia, an event which is correlated with poor survival.[12] Inducing the loss of extrachromosomally amplified genes in human tumor cells has been shown to reduce tumorigenicity, so the elimination of DMs or other ecDNA carrying oncogenes is one suggested avenue of cancer treatment research.[13]

Aside from gene amplification, DMs play a role in cancer through driving tumor evolution and treatment resistance. While DMs lack the centromeres and telomeres usually essential for subdividing chromosome material during cell division, they can segregate to the daughter cell nucleus by associating with the telomeric ends of mitotic chromosomes.[14] This process results in varied partitioning, and the unequal division in the number of DMs passed to offspring cells increases tumor heterogeneity, driving tumor evolution and increasing the chance of tumor cells acquiring a selective advantage.[15] Amplified genes, in addition to residing in DMs, can also be located in the chromosomal HSRs. Inter-conversion between DMs and HSRs has been suggested as a mechanism for chemotherapy resistance, as oncogenes targeted by drug treatment are selectively eliminated from extrachromosomal DNA but reemerge after drug withdrawal.[16]

See also

References

  1. ↑ 1.0 1.1 "Massive Genomic Rearrangement Acquired in a Single Catastrophic Event during Cancer Development". Cell 144 (1): 27–40. 2011. doi:10.1016/j.cell.2010.11.055. PMID 21215367. 
  2. ↑ 2.0 2.1 Carroll, S M; DeRose, M L; Gaudray, P; Moore, C M; Needham-Vandevanter, D R; Von Hoff, D D; Wahl, G M (April 1988). "Double minute chromosomes can be produced from precursors derived from a chromosomal deletion". Molecular and Cellular Biology 8 (4): 1525–1533. doi:10.1128/mcb.8.4.1525-1533.1988. PMID 2898098. 
  3. ↑ Van Roy, Nadine; Vandesompele, Jo; Menten, Björn; Nilsson, Helén; De Smet, Els; Rocchi, Mariano; De Paepe, Anne; Påhlman, Sven et al. (February 2006). "Translocation-excision-deletion-amplification mechanism leading to nonsyntenic coamplification ofMYC andATBF1". Genes, Chromosomes and Cancer 45 (2): 107–117. doi:10.1002/gcc.20272. PMID 16235245. 
  4. ↑ L'Abbate, Alberto; Macchia, Gemma; D'Addabbo, Pietro; Lonoce, Angelo; Tolomeo, Doron; Trombetta, Domenico; Kok, Klaas; Bartenhagen, Christoph et al. (18 August 2014). "Genomic organization and evolution of double minutes/homogeneously staining regions with MYC amplification in human cancer". Nucleic Acids Research 42 (14): 9131–9145. doi:10.1093/nar/gku590. PMID 25034695. 
  5. ↑ Iman, DS; Shay, JW (15 August 1989). "Modification of myc gene amplification in human somatic cell hybrids.". Cancer Research 49 (16): 4417–22. PMID 2568170. 
  6. ↑ Coquelle, Arnaud; Toledo, Franck; Stern, Sabine; Bieth, Anne; Debatisse, Michelle (August 1998). "A New Role for Hypoxia in Tumor Progression". Molecular Cell 2 (2): 259–265. doi:10.1016/s1097-2765(00)80137-9. PMID 9734364. 
  7. ↑ Shimizu, Noriaki; Hanada, Naoyuki; Utani, Kohichi; Sekiguchi, Naoki (1 October 2007). "Interconversion of intra- and extra-chromosomal sites of gene amplification by modulation of gene expression and DNA methylation". Journal of Cellular Biochemistry 102 (2): 515–529. doi:10.1002/jcb.21313. PMID 17390337. 
  8. ↑ Wei, J; Wu, C; Meng, H; Li, M; Niu, W; Zhan, Y; Jin, L; Duan, Y et al. (2020). "The biogenesis and roles of extrachromosomal oncogene involved in carcinogenesis and evolution.". American Journal of Cancer Research 10 (11): 3532–3550. PMID 33294253. 
  9. ↑ Lo, Anthony W.l.; Sabatier, Laure; Fouladi, Bijan; Pottier, Géraldine; Ricoul, Michelle; Mumane, John P. (2002). "DNA Amplification by Breakage/Fusion/Bridge Cycles Initiated by Spontaneous Telomere Loss in a Human Cancer Cell Line". Neoplasia 4 (6): 531–538. doi:10.1038/sj.neo.7900267. PMID 12407447. 
  10. ↑ Movafagh, A; Mirfakhraei, R; Mousavi-Jarrahi, A (2011). "Frequent incidence of double minute chromosomes in cancers, with special up-to-date reference to leukemia.". Asian Pacific Journal of Cancer Prevention 12 (12): 3453–6. PMID 22471496. 
  11. ↑ Shimizu, N (28 September 2021). "Gene Amplification and the Extrachromosomal Circular DNA.". Genes 12 (10): 1533. doi:10.3390/genes12101533. PMID 34680928. 
  12. ↑ Wong, KF; Siu, LL; Wong, WS (February 2014). "Double minutes and MYC amplification: a combined May-Grunwald Giemsa and fluorescence in situ hybridization study.". American Journal of Clinical Pathology 141 (2): 280–4. doi:10.1309/AJCPWUBGT7C0LHIN. PMID 24436278. 
  13. ↑ Von Hoff, DD; McGill, JR; Forseth, BJ; Davidson, KK; Bradley, TP; Van Devanter, DR; Wahl, GM (1 September 1992). "Elimination of extrachromosomally amplified MYC genes from human tumor cells reduces their tumorigenicity.". Proceedings of the National Academy of Sciences of the United States of America 89 (17): 8165–9. doi:10.1073/pnas.89.17.8165. PMID 1518843. 
  14. ↑ Kanda, T; Otter, M; Wahl, GM (January 2001). "Mitotic segregation of viral and cellular acentric extrachromosomal molecules by chromosome tethering.". Journal of Cell Science 114 (Pt 1): 49–58. doi:10.1242/jcs.114.1.49. PMID 11112689. 
  15. ↑ Verhaak, RGW; Bafna, V; Mischel, PS (May 2019). "Extrachromosomal oncogene amplification in tumour pathogenesis and evolution.". Nature Reviews. Cancer 19 (5): 283–288. doi:10.1038/s41568-019-0128-6. PMID 30872802. 
  16. ↑ Nathanson, DA; Gini, B; Mottahedeh, J; Visnyei, K; Koga, T; Gomez, G; Eskin, A; Hwang, K et al. (3 January 2014). "Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA.". Science 343 (6166): 72–6. doi:10.1126/science.1241328. PMID 24310612. Bibcode: 2014Sci...343...72N. 



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