Mammalian Chromosome Stability
Start date: Oct 1, 2012,
End date: Sep 30, 2016
Accurate DNA recombination is critical for preventing tumorigenesis and developmental defects. In normal cells, the DNA damage response helps prevent the propagation cells with aberrant chromosome content. It is known that DNA repair often compromised in tumor cells, but much remains to be discovered about its regulation on the molecular level. For instance, how much cell-to-cell or patient-to-patient variation is there in the type and frequency of DNA rearrangements? What puts certain genomic areas at risk for germline rearrangements?We will address these questions by examining in vivo outcomes of recombination-based DNA repair . Since genomic rearrangements can arise during both mitotic and meiotic cell divisions, and many central proteins have conserved roles in mitosis and meiosis, both systems will be studied. Sensitive PCR methods will be used that enable the detection of rare de novo DNA configurations directly from primary (uncultured) cells. We will complement these assays by immuno-FISH microscopy, to investigate both chromosome dynamics and the localization of proteins of interest within the nucleus.These studies will provide insights into how cells repair broken DNA. This fundamental process is essential for the faithful transmission of DNA into daughter cells. In the long term, understanding the underlying molecular mechanisms could pave the way to safer, more personalized cancer therapies.
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