Open AccessHuman genetic marker for resistance to radiations and chemicals. 1998 annual progress report
Author(s) -
Howard B. Lieberman
Publication year - 1998
Language(s) - English
Resource type - Reports
DOI - 10.2172/13594
Subject(s) - schizosaccharomyces pombe , biology , dna repair , dna damage , dna replication , dna , g2 m dna damage checkpoint , schizosaccharomyces , mitosis , yeast , mutant , cell cycle , gene , genetics , microbiology and biotechnology , cell cycle checkpoint , computational biology
'The broad objective of the project is to understand the molecular basis for the response of cells to radiations and chemicals, with the pragmatic goal of being able to identify human subpopulations that are exceptionally sensitive to DNA damaging agents. The project focuses on HRAD9, a human orthologue of the fission yeast Schizosaccharomyces pombe gene rad9. S. pombe rad9::ura4+ mutant cells are highly sensitive to ionizing radiation, UV and many chemicals, such as the DNA synthesis inhibitor hydroxyurea. They also lack the ability to delay cycling transiently in S phase or in G2 following a block in DNA replication or after incurring DNA damage, respectively -i.e., they lack checkpoint controls. The attempt by mutant cells to progress through mitosis in the absence of fully intact DNA accounts at least in part for their sensitivity to DNA damaging agents. Cells bearing rad9::ura4+ also aberrantly regulate UVDE, an enzyme that participates in a secondary DNA excision repair pathway. The key role played by S. pombe rad9 in promoting resistance to chemicals and radiations suggests that the evolutionarily conserved human cognate also has important functions in mammals. The first set of aims in this proposal centers on characterizing the structure and expression of HRAD9, to assess structure/function relationships and potentially link protein activity to a specific tissue. The next set of aims focuses on determining the role of HRAD9 in radio/chemoresponsiveness and cancer.