The goals of this program are to elucidate basic molecular mechanisms which relate to the macromolecular behavior of DNA, its repair, recombination, and mutagenesis. This proposal incorporates seven senior investigators and their research groups into a program focussed on biochemical and molecular approaches to study of basic problems in macromolecular DNA metabolism. Studies are proposed using both procaryotic and eucaryotic systems, using model systems as well as clinically relevant approaches. In this continuation application, renewal of the five projects is proposed along with addition of two new projects. The research work proposed in this Program-Project involves biochemical and genetic experiments to study recombination, DNA repair and mutagenesis in both procaryotes and eucaryotes. Projects 3, 4 and 6 (Low, Liskay and Radding) involve study of mechanisms of recombination. In Projects 1 and 2 (Brash and Rupp) details of excision repair pathway will be studied in eucaryotic cells (Brash) and in the UVRABC system in E. coli (Rupp). Brash (Project 1) will investigate the role of oncogenes in processes of DNA repair and mutagenesis. Summers (Project 5) proposes to study the mechanisms by which DNA damage can induce new gene expression or modify pre-existing cellular activities. Hutchinson (Project 8) plans to synthesize and systematize existing data in molecular radiobiology and to develop general principles of structure-function relationships for specific types of DNA damage. It is clear that several of the projects will overlap at the conceptual level: the work of Radding, Liskay and Low all require heuristic models of genetic recombination. Enzymological and biochemical methods and approaches will be shared by Rupp, Radding, and Summers. Pathways of excision repair and molecular models will guide the approaches of both Rupp and Brash, while the work proposed by Hutchinson will draw upon, and potentially contribute to, all the components of the Program.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA039238-08
Application #
2089790
Study Section
Special Emphasis Panel (SRC (N1))
Project Start
1986-01-01
Project End
1996-03-31
Budget Start
1994-04-01
Budget End
1995-03-31
Support Year
8
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Yale University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520
Li, Z; Karakousis, G; Chiu, S K et al. (1998) The beta protein of phage lambda promotes strand exchange. J Mol Biol 276:733-44
Karakousis, G; Ye, N; Li, Z et al. (1998) The beta protein of phage lambda binds preferentially to an intermediate in DNA renaturation. J Mol Biol 276:721-31
Kovalenko, O V; Golub, E I; Bray-Ward, P et al. (1997) A novel nucleic acid-binding protein that interacts with human rad51 recombinase. Nucleic Acids Res 25:4946-53
Gupta, R C; Bazemore, L R; Golub, E I et al. (1997) Activities of human recombination protein Rad51. Proc Natl Acad Sci U S A 94:463-8
Reddy, G; Golub, E I; Radding, C M (1997) Human Rad52 protein promotes single-strand DNA annealing followed by branch migration. Mutat Res 377:53-9
Hutchinson, F (1997) Calculation by microdosimetric methods of the formation by a single high-energy photon or electron of two lesions in the same DNA molecule. Int J Radiat Biol 71:485-6
Chiu, S K; Low, K B; Yuan, A et al. (1997) Resolution of an early RecA-recombination intermediate by a junction-specific endonuclease. Proc Natl Acad Sci U S A 94:6079-83
Golub, E I; Kovalenko, O V; Gupta, R C et al. (1997) Interaction of human recombination proteins Rad51 and Rad54. Nucleic Acids Res 25:4106-10
Hutchinson, F (1996) Formation of two double-strand breaks in the same DNA molecule by a single high-energy photon or ionizing particle. Int J Radiat Biol 70:505-12
Kovalenko, O V; Plug, A W; Haaf, T et al. (1996) Mammalian ubiquitin-conjugating enzyme Ubc9 interacts with Rad51 recombination protein and localizes in synaptonemal complexes. Proc Natl Acad Sci U S A 93:2958-63

Showing the most recent 10 out of 41 publications