Replication stress generates distinctive landscapes of DNA copy number alterations and chromosome scale losses.
Replication stress generates distinctive landscapes of DNA copy number alterations and chromosome scale losses.
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DOI：
10.1186/s13059-022-02781-0
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发表时间：
2022-10-20
期刊：
影响因子：
12.3
通讯作者：
中科院分区：
文献类型：
--
作者：
癌症染色体不稳定性的一个主要驱动因素是复制压力，即DNA复制的减缓或停滞。复制应激和基因组不稳定性是如何联系在一起的尚不清楚。Aphidicolin诱导的复制应激诱导常见脆性位点的断裂，但脆性的确切原因是有争议的，复制应激的急性基因组后果没有得到充分探讨。我们的特点DNA拷贝数改变（CNAs）在单一的，二倍体非转化细胞，所造成的一个细胞周期中存在的阿非迪霉素或羟基脲。产生了多种类型的CNA，与不同的基因组区域和特征相关，并且观察到的拷贝数景观在蚜虫菌素和羟基脲诱导的复制应激之间是不同的。耦合细胞类型特异性分析的CNAs的基因表达和单细胞复制定时分析，查明了最经常发生的染色体规模的CNAs在aphidicolin的致病大基因。它们在RPE 1上皮细胞中聚集在7号染色体上，但在BJ成纤维细胞中聚集在1号染色体上。染色体臂水平CNA也产生含有这些染色体的无着丝粒落后染色质和微核。由复制应激驱动的染色体不稳定性通过局灶性CNA和染色体臂尺度变化发生，后者局限于染色体区域的非常小的子集，可能严重扭曲癌症基因组进化。不同的复制应激诱导剂导致独特的CNA景观，提供了获得特定复制应激机制的拷贝数签名的机会。因此，单细胞CNA分析揭示了复制应激对基因组的影响，为癌症中染色体不稳定性的分子机制提供了见解。在线版本包含补充材料，可通过10.1186/s13059-022-02781-0获得。
A major driver of cancer chromosomal instability is replication stress, the slowing or stalling of DNA replication. How replication stress and genomic instability are connected is not known. Aphidicolin-induced replication stress induces breakages at common fragile sites, but the exact causes of fragility are debated, and acute genomic consequences of replication stress are not fully explored. We characterize DNA copy number alterations (CNAs) in single, diploid non-transformed cells, caused by one cell cycle in the presence of either aphidicolin or hydroxyurea. Multiple types of CNAs are generated, associated with different genomic regions and features, and observed copy number landscapes are distinct between aphidicolin and hydroxyurea-induced replication stress. Coupling cell type-specific analysis of CNAs to gene expression and single-cell replication timing analyses pinpointed the causative large genes of the most recurrent chromosome-scale CNAs in aphidicolin. These are clustered on chromosome 7 in RPE1 epithelial cells but chromosome 1 in BJ fibroblasts. Chromosome arm level CNAs also generate acentric lagging chromatin and micronuclei containing these chromosomes. Chromosomal instability driven by replication stress occurs via focal CNAs and chromosome arm scale changes, with the latter confined to a very small subset of chromosome regions, potentially heavily skewing cancer genome evolution. Different inducers of replication stress lead to distinctive CNA landscapes providing the opportunity to derive copy number signatures of specific replication stress mechanisms. Single-cell CNA analysis thus reveals the impact of replication stress on the genome, providing insights into the molecular mechanisms which fuel chromosomal instability in cancer. The online version contains supplementary material available at 10.1186/s13059-022-02781-0.
影响因子：
5.6
作者：
Courtot L;Bournique E;Maric C;Guitton-Sert L;Madrid-Mencía M;Pancaldi V;Cadoret JC;Hoffmann JS;Bergoglio V
通讯作者：
Bergoglio V