The Function and Production of eccDNA
Paulsen, Teressa, Biochemistry and Molecular Genetics - School of Medicine, University of Virginia
Paulsen, Teressa, MD-BIOC Biochem/Mole Genetics, University of Virginia
The hallmark of oncogenesis is genetic alterations that lead to unregulated cell proliferation and migration. One type of genetic alteration is the excision or copying of DNA from the chromosome body during DNA repair followed by ligation of the non-chromosomal DNA to form extrachromosomal circular DNA (eccDNA). DNA sequences within eccDNA can become greatly amplified through non-Mendelian inheritance, which can lead to changes in the expression of genes within the DNA sequence, including full protein coding genes as well as non-coding microRNA and novel si-like RNA. This leads to changes in gene expression within the cell, increasing the heterogeneity and adaptability of a population of cancer cells.
EccDNA formation occurs through resection-dependent DNA repair pathways which utilize microhomology-mediated end joining and trigger mismatch repair pathways. Conversely, non-homologous blunt end joining of DNA double strand breaks on the chromosome represses the formation of eccDNA. The formation of eccDNA is tied to double strand breaks (DSBs) in the genome and to replication, and eccDNAs are produced most during S-phase. These data suggest that eccDNA forms naturally as a result of breaks of DNA during replication. I hypothesize that when DNA at the end of a break is resected, the resulting single strand sequence anneals back to itself, or to a sister-chromatid, and forms mismatches and looped structures in the DNA that give rise to eccDNA. These observations can help improve cancer treatment strategies by providing targets for decreasing eccDNA formation and thus decrease tumor adaptation and growth.
PHD (Doctor of Philosophy)
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