Michael Smith Laboratories, University of British Columbia, Vancouver, Canada.
PLoS Genet. 2011 Apr;7(4):e1002057. doi: 10.1371/journal.pgen.1002057. Epub 2011 Apr 28.
Chromosome instability (CIN) is observed in most solid tumors and is linked to somatic mutations in genome integrity maintenance genes. The spectrum of mutations that cause CIN is only partly known and it is not possible to predict a priori all pathways whose disruption might lead to CIN. To address this issue, we generated a catalogue of CIN genes and pathways by screening ∼ 2,000 reduction-of-function alleles for 90% of essential genes in Saccharomyces cerevisiae. Integrating this with published CIN phenotypes for other yeast genes generated a systematic CIN gene dataset comprised of 692 genes. Enriched gene ontology terms defined cellular CIN pathways that, together with sequence orthologs, created a list of human CIN candidate genes, which we cross-referenced to published somatic mutation databases revealing hundreds of mutated CIN candidate genes. Characterization of some poorly characterized CIN genes revealed short telomeres in mutants of the ASTRA/TTT components TTI1 and ASA1. High-throughput phenotypic profiling links ASA1 to TTT (Tel2-Tti1-Tti2) complex function and to TORC1 signaling via Tor1p stability, consistent with the role of TTT in PI3-kinase related kinase biogenesis. The comprehensive CIN gene list presented here in principle comprises all conserved eukaryotic genome integrity pathways. Deriving human CIN candidate genes from the list allows direct cross-referencing with tumor mutational data and thus candidate mutations potentially driving CIN in tumors. Overall, the CIN gene spectrum reveals new chromosome biology and will help us to understand CIN phenotypes in human disease.
染色体不稳定性 (CIN) 在大多数实体瘤中都有观察到，与基因组完整性维持基因的体细胞突变有关。导致 CIN 的突变谱只有部分已知，并且不可能预先预测所有可能导致 CIN 的中断途径。为了解决这个问题，我们通过筛选酿酒酵母中 90%必需基因的约 2000 个功能降低等位基因，生成了一个 CIN 基因和途径目录。将这与其他酵母基因的已发表 CIN 表型整合在一起，生成了一个由 692 个基因组成的系统 CIN 基因数据集。丰富的基因本体论术语定义了细胞 CIN 途径，这些途径与序列同源物一起，创建了一个人类 CIN 候选基因列表，我们将其与已发表的体细胞突变数据库交叉引用，揭示了数百个突变的 CIN 候选基因。对一些特征不明显的 CIN 基因的特征分析表明，ASTRA/TTT 组件 TTI1 和 ASA1 的突变体中端粒较短。高通量表型分析将 ASA1 与 TTT（Tel2-Tti1-Tti2）复合物功能以及通过 Tor1p 稳定性与 TORC1 信号联系起来，这与 TTT 在 PI3-激酶相关激酶生物发生中的作用一致。这里提出的全面 CIN 基因列表原则上包括所有保守的真核基因组完整性途径。从列表中推导人类 CIN 候选基因允许与肿瘤突变数据直接交叉引用，从而候选突变可能在肿瘤中驱动 CIN。总的来说，CIN 基因谱揭示了新的染色体生物学，并将帮助我们理解人类疾病中的 CIN 表型。
