Systematic over-expression screens for chromosome instability identify conserved dosage chromosome instability genes in yeast and human tumors

BioRxiv : the Preprint Server for Biology
Supipi DuffyPhillip Hieter

Abstract

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...Continue Reading

Related Concepts

Malignant Neoplasms
DNA Repair
Gene Expression
Genes
Neoplasms
Rhabdomyosarcoma
Yeasts
Cnr protein, Bacteriophage P4
Chromosome Segregation
Human Cell Line

Related Feeds

Cancer Genomics (Preprints)

Cancer genomics employ high-throughput technologies to identify the complete catalog of somatic alterations that characterize the genome, transcriptome and epigenome of cohorts of tumor samples. Discover the latest preprints here.

BioRxiv & MedRxiv Preprints

BioRxiv and MedRxiv are the preprint servers for biology and health sciences respectively, operated by Cold Spring Harbor Laboratory. Here are the latest preprint articles (which are not peer-reviewed) from BioRxiv and MedRxiv.

Cancer Genomics (Keystone)

Cancer genomics approaches employ high-throughput technologies to identify the complete catalog of somatic alterations that characterize the genome, transcriptome and epigenome of cohorts of tumor samples. Discover the latest research using such technologies in this feed.

CZI Human Cell Atlas Seed Network

The aim of the Human Cell Atlas (HCA) is to build reference maps of all human cells in order to enhance our understanding of health and disease. The Seed Networks for the HCA project aims to bring together collaborators with different areas of expertise in order to facilitate the development of the HCA. Find the latest research from members of the HCA Seed Networks here.

Related Papers

Proceedings of the National Academy of Sciences of the United States of America
Supipi DuffyPhilip Hieter
Proceedings of the National Academy of Sciences of the United States of America
Yang BianKatsumi Kitagawa
Proceedings of the National Academy of Sciences of the United States of America
Kirk J McManusPhilip Hieter
© 2021 Meta ULC. All rights reserved