Genome Integrity Discussion Group June 2010

Abstract

Pathways that Prevent Genome Instability: From Model Organisms to Human Cancer

Richard D. Kolodner, Ludwig Institute for Cancer Research, University of California San Diego

Cancer is often associated with increased genome instability. To understand the control of genome instability, we have developed a series of assays for studying spontaneous genome rearrangements (GCRs) in Saccharomyces cerevisiae and identified more than 100 genes and multiple pathways that prevent GCRs. The GCRs observed include interstitial deletions, translocations, deletion of an end of a chromosome arm associated with healing by de novo telomere addition and chromosome fusions; many rearranged chromosomes also undergo secondary rearrangements. The genes identified include those encoding: replication factors, proteins that reassemble or modify chromatin, recombination and repair proteins where the defect leads to aberrant repair, checkpoint proteins that respond to replication errors, proteins that scavenge reactive oxygen species and prevent oxidative damage to DNA, proteins thought to act on damaged replication forks and on aberrant structures generated by recombination between divergent DNA sequences, and proteins that regulate telomerase. Our hypothesis is that “DNA damage” normally occurs during DNA replication or results from cellular metabolism such as pathways that produce reactive oxygen species, possibly in combination with DNA replication. The pathways that suppress GCRs subsequently act on this damage including checkpoint functions that suppress mutagenic repair and activate non-mutagenic repair, a pathway that prevents aberrant telomere additions, and homologous recombination. In the absence of one or more of these pathways, different types of mutagenic repair occur. Alternatively, in the absence of telomerase, telomere maintenance is dependent on both recombination and checkpoint functions, and when either the recombination or checkpoint pathways are compromised increased genome instability occurs. Interestingly, there are distinct differences between the pathways that act to suppress GCRs that target single copy sequence targets compared to those that act to suppress GCRs that target repeated sequences such as segmental duplications and Ty elements in the S. cerevisiae genome. To expand our genetic analysis of the pathways that suppress genome instability, we have been using a bioinformatics approach to analyze the our results combined with published S. cerevisiae genome-wide systems biology data sets. Using this approach, we have built models of the network of genes that function in the suppression of GCRs; we are in the process of using a robotic implementation of our GCR assays to validate these models and have identified additional genes that prevent GCRs. To extend these insights to human cancer genetics, we have developed tools for identifying the human homologs of S. cerevisiae genes that suppress GCRs as well as integrate relevant human genes lacking a S. cerevisiae counterpart. We are also working with Dr. Sandro de Sousa (Ludwig Institute, Sao Paulo) to use this gene list to examine the genetics of genome instability in human cancers using available data sets on mutations and changes in copy number, epigenetic silencing and gene expression in human cancers.

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