Double minute

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Double minutes (DMs) 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. The term Double Minute originates from the visualization of these features under microscope; double because the dots were found in pairs, and minute because they were minuscule.

Contents

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

Related Research Articles

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An oncogene is a gene that has the potential to cause cancer. In tumor cells, these genes are often mutated, or expressed at high levels.

<span class="mw-page-title-main">Telomerase</span> Telomere-restoring protein active in the most rapidly dividing cells

Telomerase, also called terminal transferase, is a ribonucleoprotein that adds a species-dependent telomere repeat sequence to the 3' end of telomeres. A telomere is a region of repetitive sequences at each end of the chromosomes of most eukaryotes. Telomeres protect the end of the chromosome from DNA damage or from fusion with neighbouring chromosomes. The fruit fly Drosophila melanogaster lacks telomerase, but instead uses retrotransposons to maintain telomeres.

Extrachromosomal DNA is any DNA that is found off the chromosomes, either inside or outside the nucleus of a cell. Most DNA in an individual genome is found in chromosomes contained in the nucleus. Multiple forms of extrachromosomal DNA exist, and, while some of these serve important biological functions, they can also play a role in diseases such as cancer.

Myc is a family of regulator genes and proto-oncogenes that code for transcription factors. The Myc family consists of three related human genes: c-myc (MYC), l-myc (MYCL), and n-myc (MYCN). c-myc was the first gene to be discovered in this family, due to homology with the viral gene v-myc.

<span class="mw-page-title-main">N-Myc</span> Protein-coding gene in the species Homo sapiens

N-myc proto-oncogene protein also known as N-Myc or basic helix-loop-helix protein 37 (bHLHe37), is a protein that in humans is encoded by the MYCN gene.

<span class="mw-page-title-main">Telomerase reverse transcriptase</span> Catalytic subunit of the enzyme telomerase

Telomerase reverse transcriptase is a catalytic subunit of the enzyme telomerase, which, together with the telomerase RNA component (TERC), comprises the most important unit of the telomerase complex.

<span class="mw-page-title-main">MYC</span> Protein-coding gene in the species Homo sapiens

MYC proto-oncogene, bHLH transcription factor is a protein that in humans is encoded by the MYC gene which is a member of the myc family of transcription factors. The protein contains basic helix-loop-helix (bHLH) structural motif.

<span class="mw-page-title-main">NME2</span> Protein-coding gene in the species Homo sapiens

Nucleoside diphosphate kinase B is an enzyme that in humans is encoded by the NME2 gene.

<span class="mw-page-title-main">MYCL</span> Protein-coding gene in the species Homo sapiens

L-myc-1 proto-oncogene protein is a protein that in humans is encoded by the MYCL1 gene.

<span class="mw-page-title-main">PVT1</span> Non-coding RNA in the species Homo sapiens

Pvt1 oncogene, also known as PVT1 or Plasmacytoma Variant Translocation 1 is a long non-coding RNA gene. In mice, this gene was identified as a breakpoint site in chromosome 6;15 translocations. These translocations are associated with murine plasmacytomas. The equivalent translocation in humans is t(2;8), which is associated with a rare variant of Burkitt's lymphoma. In rats, this breakpoint was shown to be a common site of proviral integration in retrovirally induced T lymphomas. Transcription of PVT1 is regulated by Myc.

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<span class="mw-page-title-main">Chromothripsis</span> Massive chromosomal rearrangement process linked to cancer

Chromothripsis is a mutational process by which up to thousands of clustered chromosomal rearrangements occur in a single event in localised and confined genomic regions in one or a few chromosomes, and is known to be involved in both cancer and congenital diseases. It occurs through one massive genomic rearrangement during a single catastrophic event in the cell's history. It is believed that for the cell to be able to withstand such a destructive event, the occurrence of such an event must be the upper limit of what a cell can tolerate and survive. The chromothripsis phenomenon opposes the conventional theory that cancer is the gradual acquisition of genomic rearrangements and somatic mutations over time.

<span class="mw-page-title-main">ZNF703</span> Protein-coding gene in the species Homo sapiens

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<span class="mw-page-title-main">Breakage-fusion-bridge cycle</span>

Breakage-fusion-bridge (BFB) cycle is a mechanism of chromosomal instability, discovered by Barbara McClintock in the late 1930s.

Chromosomal instability (CIN) is a type of genomic instability in which chromosomes are unstable, such that either whole chromosomes or parts of chromosomes are duplicated or deleted. More specifically, CIN refers to the increase in rate of addition or loss of entire chromosomes or sections of them. The unequal distribution of DNA to daughter cells upon mitosis results in a failure to maintain euploidy leading to aneuploidy. In other words, the daughter cells do not have the same number of chromosomes as the cell they originated from. Chromosomal instability is the most common form of genetic instability and cause of aneuploidy.

Extrachromosomal circular DNA (eccDNA) is a type of double-stranded circular DNA structure that was first discovered in 1964 by Alix Bassel and Yasuo Hotta. In contrast to previously identified circular DNA structures, eccDNA are circular DNA found in the eukaryotic nuclei of plant and animal cells. Extrachromosomal circular DNA is derived from chromosomal DNA, can range in size from 50 base pairs to several mega-base pairs in length, and can encode regulatory elements and full-length genes. eccDNA has been observed in various eukaryotic species and it is proposed to be a byproduct of programmed DNA recombination events, such as V(D)J recombination.

<span class="mw-page-title-main">MicroDNA</span>

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<span class="mw-page-title-main">June Biedler</span> American scientist

June Biedler was an American scientist primarily known for her discovery of proteins that lead to resistance of cancer cells to chemotherapy. Her work has been crucial for an understanding of both the development of drug resistance and also for strategies to circumvent such resistance. In addition, Biedler made important contributions to an understanding of the molecular mechanisms of neuroblastoma development, particularly of the role of the N-myc oncogene in the genesis of neuroblastoma

References

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  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. PMC   1503667 . PMID   12407447.
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