This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The DNA damage response (DDR) pathway plays an essential tumor suppressive role ensuring the integrity of genomic information. Indeed, mutations affecting components of this pathway are common in human cancer. Despite extensive research in the DNA damage field several steps in this process remain poorly understood suggesting that crucial players in this pathway have yet to be identified. In particular, poorly characterized is the mechanism by which cells detect DNA lesions, which is the initial and crucial step for DNA damage response initiation. Two major limitations have hindered the research in this field: i) the unpredictable location of DNA damage sites induced by conventional DNA damage-inducing agents, ii) the lack of a technique for the isolation of proteins associated with a given DNA substrate. I will overcome these limitations by taking advantage of: i) telomere dysfunction as a tool to induce DNA damage to specific genomic loci, ii) a novel technique developed to isolate protein associated with specific chromatin loci termed Proteomics of Isolated Chromatin segments (PICh). Combining these two approaches I will be able to induce DNA damage on defined genomic loci in order to isolate and identify the components of the DNA damage machinery that localize to DNA damage sites. This approach is highly innovative and has the potential of identifying novel components of the DNA damage pathway in mammalian cells. Given the frequency by which mutations affecting components of this pathway are found in cancer we anticipate that the results of our study will be of great relevance in the field of genomic stability and cancer biology.
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