TA 重复序列断裂的 MMEJ 修复维持 ecDNA 与肿瘤适应性
MMEJ repair of breaks at TA repeats maintains ecDNA and cancer fitness
染色体外 DNA（ecDNA，携带癌基因扩增的环状 DNA 元件）驱动多种肿瘤的侵袭、耐药和不良预后，但其维持机制不明。研究发现，抑制微同源介导末端连接（MMEJ）而非非同源末端连接或同源重组，能选择性耗竭 ecDNA、诱发 ecDNA 特异性损伤并使其进入微核，从而削弱依赖 ecDNA 的肿瘤细胞。机制上，ecDNA 上富含 TA 的位点是断裂热点，FANCM 抑制断裂，逃逸的断裂由 ERCC1-ERCC4 切割并进入 MMEJ 修复。单细胞测序显示干扰 FANCM 或聚合酶 θ 会导致 TA 富集区的结构不稳定。该发现提示 Polθ 抑制是 destabilize ecDNA、增敏治疗的潜在策略。
为什么推荐给您：首次揭示 MMEJ/Polθ 维持 ecDNA 的机制，提出全新治疗靶点，属重大进展。
不需要生物学背景，多打比方
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摘要Abstract
Extrachromosomal DNA (ecDNA) comprises megabase-sized circular DNA elements that frequently carry oncogene amplifications, driving aggressive tumour phenotypes, therapeutic resistance and poor clinical outcomes across many cancers1-4. Although ecDNA is thought to arise from canonical double-strand break repair, the pathways that maintain it remain unclear. Here we show that inhibition of microhomology-mediated end joining, but not non-homologous end joining or homologous recombination, selectively depletes ecDNA, induces ecDNA-specific damage and promotes its sequestration into micronuclei, compromising the fitness of cancer cells that depend on ecDNA-driven oncogene amplification. Mechanistically, TA-rich loci on ecDNA are hotspots for DNA damage and breakage5,6. The DNA translocase FANCM suppresses break formation at these sites, while breaks that escape FANCM surveillance are cleaved by ERCC1-ERCC4 and channelled into microhomology-mediated end joining for repair. Single-cell whole-genome sequencing shows that disrupting FANCM or polymerase θ (Polθ) in COLO320DM cells causes structural instability characterized by deletions and small duplications, with breakpoints enriched at TA-rich regions. This fragility is recapitulated in human tumours, in which ecDNA rearrangements are enriched at TA repeats. Collectively, our findings reveal TA repeat fragility as an intrinsic vulnerability of circular DNA and identify Polθ inhibition as a promising strategy to potentially destabilize ecDNA and sensitize ecDNA-driven tumours to therapeutic intervention.