TY - JOUR T1 - Systematic over-expression screens for chromosome instability identify conserved dosage chromosome instability genes in yeast and human tumors JF - bioRxiv DO - 10.1101/038489 SP - 038489 AU - Supipi Duffy AU - Hok Kim Fam AU - Yikan Wang AU - Erin B. Styles AU - Jung-Huyn Kim AU - J. Sidney Ang AU - Tejomayee Singh AU - Vladimir Larionov AU - Sohrab Shah AU - Brenda J. Andrews AU - Cornelius Boerkel AU - Phillip Hieter Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/02/01/038489.abstract N2 - Somatic copy number amplifications (SCNAs) and gene over-expression are common features of many cancers. To determine the role of gene over-expression on genome stability, we performed functional genomic screens in the budding yeast for chromosome instability, a defining characteristic of cancer that can be targeted by therapeutics. Over-expression of 245 yeast genes increases chromosome instability by influencing processes such as chromosome segregation and DNA damage repair. Testing candidate human homologs, which were highly recurrently altered in tumors lead to the identification of 2 genes, Tdp1 and Taf12 that contribute to CIN in human cells when over-expressed. Rhabdomyosarcoma lines with higher levels of Tdp1 also show chromosome instability and can be partially rescued by siRNA-mediated knockdown of Tdp1. Using synthetic dosage lethality screens in yeast, we identified candidate target genes that will specifically target tumors with high levels of Tdp1. We demonstrate the utility of functional genetic screens in model organisms to broaden the spectrum of CIN genes, to identify novel genes relevant to chromosome instability in humans and to identify candidate gene targets that can be leveraged to selectively kill tumors over-expressing specific genes. ER -