Life of double minutes: generation, maintenance, and elimination

Abstract

Advances in genome sequencing have revealed a type of extrachromosomal DNA, historically named double minutes (also referred to as ecDNA), to be common in a wide range of cancer types, but not in healthy tissues. These cancer-associated circular DNA molecules contain one or a few genes that are amplified when double minutes accumulate. Double minutes harbor oncogenes or drug resistance genes that contribute to tumor aggressiveness through copy number amplification in combination with favorable epigenetic properties. Unequal distribution of double minutes over daughter cells contributes to intratumoral heterogeneity, thereby increasing tumor adaptability. In this review, we discuss various models delineating the mechanism of generation of double minutes. Furthermore, we highlight how double minutes are maintained, how they evolve, and discuss possible mechanisms driving their elimination.

Extrachromosomal circular DNA landscape of breast cancer with lymph node metastasis

“…16,18,36 eccDNA extends its presence beyond tumor cells, being detectable within the extracellular space, where it potentially influences the TIME and intercellular communication. 37,38 This finding indicates a broader role for eccDNA in cancer biology, linking it to essential processes such as tumor evolution, the development of drug resistance, and an elevated tumor mutation burden.…”

Insights into the Clinical, Biological and Therapeutic Impact of Copy Number Alteration in Cancer

“…Additionally, chromothripsis is one of the mechanisms that can lead to the release of extrachromosomal material (Figure 2D). ecDNA usually involves double stranded breaks, replication and circularisation of small fragments that contain one or a few genes and exist separately to chromosomes (Figure 2E) [52]. These ecDNA are commonly found in cancer and a recent observation has shown that oncogene overexpression through ecDNA formation contributes to tumour heterogeneity and genome evolution during cancer progression [53].…”

Extrachromosomal circular DNA in colorectal cancer: biogenesis, function and potential as therapeutic target

“…Migration of ecDNA molecules into the same daughter cell after mitosis indicates that there are presumable post-replication bonds [ 68 ]. Several mechanisms for eliminating ecDNA have been proposed, such as physical exclusion from the cell, enzymatic degradation, and the elimination of micronucleated cells by cell death [ 69 ]. ecDNA can be removed from the nucleus by a micronucleation mechanism that initiates budding of the nuclear membrane during the S phase of mitosis in CRC cells [ 66 ] (Fig.…”