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Microsatellite break-induced replication generates highly mutagenized extrachromosomal circular DNAs

NAR Cancer, ISSN: 2632-8674, Vol: 6, Issue: 2, Page: zcae027
2024
  • 2
    Citations
  • 0
    Usage
  • 7
    Captures
  • 1
    Mentions
  • 0
    Social Media
Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    2
  • Captures
    7
  • Mentions
    1
    • News Mentions
      1
      • 1

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Research Findings from Wright State University Update Understanding of Cancer Research (Microsatellite break-induced replication generates highly mutagenized extrachromosomal circular DNAs)

2024 JUN 24 (NewsRx) -- By a News Reporter-Staff News Editor at Cancer Daily -- Investigators publish new report on cancer research. According to news

Article Description

Extrachromosomal circular DNAs (eccDNAs) are produced from all regions of the eucaryotic genome. We used inverse PCR of non-B microsatellites capable of forming hairpin, triplex, quadruplex and AT-rich structures integrated at a common ectopic chromosomal site to show that these non-B DNAs generate highly mutagenized eccDNAs by replication-dependent mechanisms. Mutagenesis occurs within the non-B DNAs and extends several kilobases bidirectionally into flanking and nonallelic DNA. Each non-B DNA exhibits a different pattern of mutagenesis, while sister clones containing the same non-B DNA also display distinct patterns of recombination, microhomology-mediated template switching and base substitutions. Mutations include mismatches, short duplications, long nontemplated insertions, large deletions and template switches to sister chromatids and nonallelic chromosomes. Drug-induced replication stress or the depletion of DNA repair factors Rad51, the COPS2 signalosome subunit or POLηchange the pattern of template switching and alter the eccDNA mutagenic profiles. We propose an asynchronous capture model based on break-induced replication from microsatellite-induced DNA double strand breaks to account for the generation and circularization of mutagenized eccDNAs and the appearance of genomic homologous recombination deficiency (HRD) scars. These results may help to explain the appearance of tumor eccDNAS and their roles in neoantigen production, oncogenesis and resistance to chemotherapy.

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