Mutability and mutational spectrum of chromosome transmission fidelity genes |
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Authors: | Peter C Stirling Matthew J Crisp Munira A Basrai Cheryl M Tucker Maitreya J Dunham Forrest A Spencer Philip Hieter |
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Institution: | (1) Michael Smith Laboratories, University of British Columbia, Vancouver, BC, Canada, V6T1Z4;(2) Genetics Branch Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA;(3) Lewis-Sigler Institute, Princeton University, Princeton, NJ 08544, USA;(4) Department of Genome Sciences, University of Washington, School of Medicine, Seattle, WA 98195, USA;(5) McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA; |
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Abstract: | It has been more than two decades since the original chromosome transmission fidelity (Ctf) screen of Saccharomyces cerevisiae was published. Since that time the spectrum of mutations known to cause Ctf and, more generally, chromosome instability (CIN)
has expanded dramatically as a result of systematic screens across yeast mutant arrays. Here we describe a comprehensive summary
of the original Ctf genetic screen and the cloning of the remaining complementation groups as efforts to expand our knowledge
of the CIN gene repertoire and its mutability in a model eukaryote. At the time of the original screen, it was impossible
to predict either the genes and processes that would be overrepresented in a pool of random mutants displaying a Ctf phenotype
or what the entire set of genes potentially mutable to Ctf would be. We show that in a collection of 136 randomly selected
Ctf mutants, >65% of mutants map to 13 genes, 12 of which are involved in sister chromatid cohesion and/or kinetochore function.
Extensive screening of systematic mutant collections has shown that ~350 genes with functions as diverse as RNA processing
and proteasomal activity mutate to cause a Ctf phenotype and at least 692 genes are required for faithful chromosome segregation.
The enrichment of random Ctf alleles in only 13 of ~350 possible Ctf genes suggests that these genes are more easily mutable
to cause genome instability than the others. These observations inform our understanding of recurring CIN mutations in human
cancers where presumably random mutations are responsible for initiating the frequently observed CIN phenotype of tumors. |
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