Preparing your results

Our searching services are busy right now. Your search will reload in five seconds.

X
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.

Saccharomyces cerevisiae genetics predicts candidate therapeutic genetic interactions at the mammalian replication fork.

G3 (Bethesda, Md.) | Feb 7, 2013

The concept of synthetic lethality has gained popularity as a rational guide for predicting chemotherapeutic targets based on negative genetic interactions between tumor-specific somatic mutations and a second-site target gene. One hallmark of most cancers that can be exploited by chemotherapies is chromosome instability (CIN). Because chromosome replication, maintenance, and segregation represent conserved and cell-essential processes, they can be modeled effectively in simpler eukaryotes such as Saccharomyces cerevisiae. Here we analyze and extend genetic networks of CIN cancer gene orthologs in yeast, focusing on essential genes. This identifies hub genes and processes that are candidate targets for synthetic lethal killing of cancer cells with defined somatic mutations. One hub process in these networks is DNA replication. A nonessential, fork-associated scaffold, CTF4, is among the most highly connected genes. As Ctf4 lacks enzymatic activity, potentially limiting its development as a therapeutic target, we exploited its function as a physical interaction hub to rationally predict synthetic lethal interactions between essential Ctf4-binding proteins and CIN cancer gene orthologs. We then validated a subset of predicted genetic interactions in a human colorectal cancer cell line, showing that siRNA-mediated knockdown of MRE11A sensitizes cells to depletion of various replication fork-associated proteins. Overall, this work describes methods to identify, predict, and validate in cancer cells candidate therapeutic targets for tumors with known somatic mutations in CIN genes using data from yeast. We affirm not only replication stress but also the targeting of DNA replication fork proteins themselves as potential targets for anticancer therapeutic development.

Pubmed ID: 23390603 RIS Download

Mesh terms: Chromosomal Instability | Colorectal Neoplasms | DNA Replication | DNA-Binding Proteins | Gene Regulatory Networks | Genes, Essential | Genome, Fungal | HCT116 Cells | Humans | Mutagens | Mutation | RNA Interference | RNA, Small Interfering | Saccharomyces cerevisiae | Saccharomyces cerevisiae Proteins

Research resources used in this publication

None found

Research tools detected in this publication

Data used in this publication

None found

Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA158162
  • Agency: Canadian Institutes of Health Research, Id:

BioGRID (Data, Interactions)

Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.

This is a list of tools and resources that we have found mentioned in this publication.


ImageJ

A Java image processing program which can display, edit, analyze, process, save and print 8-bit, 16-bit and 32-bit images. It can read many image formats including TIFF, GIF, JPEG, BMP, DICOM, FITS and raw. It runs, either as an online applet or as a downloadable application, on any computer with a Java 1.4 or later virtual machine. Downloadable distributions are available for Windows, Mac OS, Mac OS X and Linux. It supports stacks, a series of images that share a single window. It is multithreaded, so time-consuming operations such as image file reading can be performed in parallel with other operations. It can calculate area and pixel value statistics of user-defined selections. It can measure distances and angles. It can create density histograms and line profile plots. It supports standard image processing functions such as contrast manipulation, sharpening, smoothing, edge detection and median filtering. It does geometric transformations such as scaling, rotation and flips. Image can be zoomed up to 32:1 and down to 1:32. All analysis and processing functions are available at any magnification factor. The program supports any number of windows (images) simultaneously, limited only by available memory. Spatial calibration is available to provide real world dimensional measurements in units such as millimeters. Density or gray scale calibration is also available. ImageJ was designed with an open architecture that provides extensibility via Java plugins. Custom acquisition, analysis and processing plugins can be developed using ImageJ built in editor and Java compiler. User-written plugins make it possible to solve almost any image processing or analysis problem.

tool

View all literature mentions

SGD

A curated database that provides comprehensive integrated biological information for Saccharomyces cerevisiae along with search and analysis tools to explore these data. SGD allows researchers to discover functional relationships between sequence and gene products in fungi and higher organisms. The SGD also maintains the S. cerevisiae Gene Name Registry, a complete list of all gene names used in S. cerevisiae which includes a set of general guidelines to gene naming. Protein Page provides basic protein information calculated from the predicted sequence and contains links to a variety of secondary structure and tertiary structure resources. Yeast Biochemical Pathways allows users to view and search for biochemical reactions and pathways that occur in S. cerevisiae as well as map expression data onto the biochemical pathways. Literature citations are provided where available.

tool

View all literature mentions