The broad objective of this proposal is to understand the role of chromatin structure in the processes of carcinogen-induced damage to DNA and its repair in human cells. Our previous studies indicate that the constraints placed upon DNA in chromatin may play an important role in the distribution of excision repair in the human genome following damage by UV radiation and """"""""UV-mimetic"""""""" chemical carcinogens. Furthermore, rearrangements of chromatin structure appear to be an obligatory final step in the excision repair process following damage by these """"""""long patch"""""""" agents. One of the objectives of the present application is to extend these studies to the repair of """"""""short patch"""""""" agents (i.e., Gamma radiation and bleomycin) in both normal human cells and human cells deficient in the repair of UV radiation and UV-mimetic agens (i.e., xeroderma pigmentosum human cells). Furthermore, we plan to carry out detailed investigations on the structure, composition and repair patch size of newly repaired regions of DNA within the chromatin of both normal and (partially) repair deficient human cells. These studies will include methods to examine the proteins directly associated with newly repaired regions of human DNA and should allow the identification of both enzymes and structural proteins involved in the repair process. These studies will also be directed at identifying similarities and differences in the protein composition of newly repaired regions in xeroderma pigmentosum human cells. Another objective of this proposal is to carry out a detailed, systematic study of the relationship of two chromatin modification events (i.e., histone acetylation and phosphorylation) and the processes of carcinogen-induced DNA damage and DNA repair in human cells. These studies will examine the levels of histone acetylation and phosphorylation in both normal and xeroderma pigmentosum human cells following treatment with the two different """"""""classes"""""""" of DNA damaging agents.
Showing the most recent 10 out of 34 publications
