Copy Number Gains (CNGs) lead to genetic heterogeneity, driving evolution and carcinogenesis. The mechanisms promoting CNG formation however remain poorly characterized. We show that abnormal expression of the replication licensing factor Cdc18 in fission yeast, which leads to genome-wide re-replication, drives the formation of CNGs at different genomic loci, promoting the acquisition of new selectable traits. Whole genome sequencing reveals Mb long, primarily extrachromosomal amplicons. Genetic analysis shows that homology-mediated repair is required to resolve re-replication intermediates into heritable CNGs. Consistently, we show that in mammalian cells overexpression of CDC6 and/or CDT1 leads to CNGs and promotes drug resistance. In human cells, multiple repair pathways are activated upon rereplication and act antagonistically, with RAD52 promoting and 53BP1 inhibiting CNG formation. In tumours, CDT1 and/or CDC6 overexpression correlates with copy number gains genome-wide. We propose re-replication as an evolutionary-conserved driver of CNGs, highlighting a link between aberrant licensing, CNGs and cancer.

中文翻译：

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异常的复制许可驱动物种间的拷贝数增长

复制数增益（CNG）导致遗传异质性，驱动进化和致癌作用。然而，促进CNG形成的机制仍知之甚少。我们显示裂变酵母中复制许可因子Cdc18的异常表达，导致全基因组重复复制，驱动不同基因组基因座上的CNG的形成，促进新的可选性状的获得。全基因组测序显示Mb长，主要是染色体外扩增子。遗传分析表明，同源介导的修复是将中间体复制成可遗传CNG所必需的。一致地，我们表明在哺乳动物细胞中CDC6和/或CDT1的过度表达导致CNG并促进耐药性。在人类细胞中，多种修复途径在复制后会被激活并起拮抗作用，与RAD52促进和53BP1抑制CNG形成。在肿瘤中，CDT1和/或CDC6的过度表达与全基因组拷贝数的增加有关。我们建议将复制作为CNG的进化保守驱动器，强调异常许可，CNG和癌症之间的联系。