The objective of the proposed work is to test 2 hypotheses regarding proteins whose nuclear matrix (NM) association is modified by heat shock (i.e., HMNMP, hyperthermia modifiable NM proteins). Hypothesis 1 is that HMNMP are involved in S phase-dependent nonhistone damage leading to cell death. Hypothesis 2 is that HMNMP inhibit DNA repair thereby causing radiosensitization. A model or Hypothesis 1 is that the HMNMPs cause a potentially lethal lesion which is either repaired by molecular chaperonins, (e.g., hsp7O, hsc7O, etc) or is fixed by progression of cells through S phase. A model for Hypothesis 2 is that HMNMP alter DNA-NM anchoring regions thereby altering the ability of DNA to undergo supercoiling changes and limiting access of repair complexes to damaged sites. Further, the proposed work will clarify relationships between charges in the amounts of specific HMNMP and heat effects such as inhibition of DNA replication, RNA processing, etc. which are largely undocumented. Specifically, the aims are as follows: 1. Identify or characterize the HMNMPs, determine their in situ localization and if they are associated with nuclear proteins involved in specific nuclear processes. 2. Determine the kinetics of NM association of the proteins characterized in Aim 1 as a function of heating time and kinetics of dissociation as a function of post heat incubation at 37 degrees C. 3. Determine which, if any, of the proteins characterized in Aims 1 and 2 remain abnormally associated, post heat, with the NM when cells resume DNA synthesis, complete DNA synthesis and when events associated with cellular necrosis have begun. 4. Determine if the amounts of the proteins defined in Aim 3 or the fraction of cells with these proteins vary in a manner which correlates with variations in survival following the manipulation of the onset of DNA synthesis post heat shock and intrinsic heat resistance. Manipulate the onset of DNA synthesis post heat shock and intrinsic heat resistance and determine if the amounts of the proteins defined in Aim 3 vary in a manner which correlates with variations in survival. 5. Determine which, if any, of the proteins characterized in Aims 1 and 2 are involved in the inhibition of repair of radiation-induced DNA damage, the ability of nuclear DNA to undergo supercoiling changes and if these HMNMP are involved in the matrix-DNA anchoring regions.

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National Cancer Institute (NCI)
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Radiation Study Section (RAD)
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Washington University
Schools of Medicine
Saint Louis
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