Abstract
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.
Highlights
Chromosome instability (CIN), involving the unequal distribution of DNA to daughter cells upon mitosis, is observed in the majority of solid tumors
High-throughput screens for genome integrity are becoming a reality in human cells, the spectrum of human mutations that lead to CIN in tumors is only partially characterized [4]
An ideal role for model organism genetics would be to identify all cellular processes whose disruption can lead to a CIN phenotype, enabling identification and functional studies of candidate genes to focus on particular mutations among those found in a tumor genome
Summary
Chromosome instability (CIN), involving the unequal distribution of DNA to daughter cells upon mitosis, is observed in the majority of solid tumors. Previous CIN screens of non-essential gene deletions have catalogued the increased frequency of chromosome transmission fidelity (CTF), A-like faker (ALF), Bi-mater (BiM), loss of heterozygosity (LOH), and gross-chromosomal rearrangements (GCR) phenotypes [5,9,10,11,12,13]. All of these phenotypes are considered CIN phenotypes as measured by an increase in the rate of marker loss the mechanisms predominant in each assay differ. Since non-essential genes have been saturated with genome instability screens, a
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