RT Journal Article
SR Electronic
T1 Systematic over-expression screens for chromosome instability identify conserved dosage chromosome instability genes in yeast and human tumors
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 038489
DO 10.1101/038489
A1 Supipi Duffy
A1 Hok Khim Fam
A1 Yikan Wang
A1 Erin B. Styles
A1 Jung-Huyn Kim
A1 J. Sidney Ang
A1 Tejomayee Singh
A1 Vladimir Larionov
A1 Sohrab Shah
A1 Brenda J. Andrews
A1 Cornelius F. Boerkoel
A1 Phillip Hieter
YR 2016
UL http://biorxiv.org/content/early/2016/02/03/038489.abstract
AB 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.