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Genome Integrity Discussion Group June 2010
Monday, June 7, 2010
The New York Academy of Sciences
Maintaining the stability of genetic information coded in DNA is an important part of the cell cycle. How the cell does so is pertinent to many human disease states, including cancer, which can result from damage to the genome. The Genome Integrity Discussion Group fosters interactions between groups working on subjects including DNA replication, transcription, chromatin modification, recombination, DNA damage responses, cell cycle control, site-specific recombination, transposition, meiosis, mitosis, telomeres, chromosome segregation, epigenetic states, and new technologies relevant to research in genome integrity. The informal format of this group includes talks by students, postdocs, and junior and senior investigators. This provides an opportunity to exchange ideas, network, and form research collaborations among scientists active in the field.
This special end-of-year meeting features keynote speaker Richard D. Kolodner (Ludwig Institute for Cancer Research, University of California San Diego) and will also include a selection of short presentations given by graduate students and postdocs, as well as a poster session.
Agenda
Pathways that Prevent Genome Instability: From Model Organisms to Human Cancer
Richard D. Kolodner, Ludwig Institute for Cancer Research, University of California San Diego
Break and Poster Setup
Contributed Presentations
Poster Presentations
Speakers
Organizers
Titia de Lange
The Rockefeller University
Rodney Rothstein
Columbia University Medical Center
John Petrini
Memorial Sloan-Kettering Cancer Center
Keynote Speaker
Richard Kolodner
Ludwig Institute for Cancer Research, University of California San Diego
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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