Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - DiVineGenoMe (Decoding cell-to-cell variation in genome integrity maintenance)

Teaser

When DNA gets damaged, this can lead to mutations and cause disease. DNA repair mechanisms have thus evolved to sense and repair DNA lesions. These mechanisms are often subverted in human cancers, indicating that defective DNA damage recognition and repair is linked to the...

Summary

When DNA gets damaged, this can lead to mutations and cause disease. DNA repair mechanisms have thus evolved to sense and repair DNA lesions. These mechanisms are often subverted in human cancers, indicating that defective DNA damage recognition and repair is linked to the accumulation of cancer-driving mutations. It is becoming increasingly clear that individual cells do not always respond equally well to genotoxic stress and DNA damage. Such cell-to-cell variability may affect cancer development, disease progression and the response to therapy. Not much is known, however, about the cellular and molecular determinants of cell-to-cell variability in the DNA damage response. This project aims at identifying determinants of heterogeneity in the cellular response to genotoxic stress and at characterizing their molecular functions.

Work performed

During the initial phase of this project, cellular heterogeneity in the response to genotoxic stress and DNA damage has been characterized and quantified at multiple levels of the DNA damage response, and new tools, in particular cell lines and cell-based assays, have been developed. First pilot siRNA screens were performed to identify potential determinants of cellular variability in the DNA damage response.

Final results

It is expected that this project will reveal new insights into the cell-to-cell variation of genotoxic stress responses. Newly developed, genetically engineered cell lines and quantitative high-content microscopy-based readouts in conjunction with custom-built computational tools for advanced image analysis provide the technological basis of this project. The experimental results and biological concepts derived from this project may help guide targeted cancer therapy.