Radiation therapy is an important treatment modality for cancer patients and is used for treating a wide variety of different tumor types. Most (more than 70%) of the DNA damages produced by ionizing radiation during treatment are those repaired by the base excision repair system and ablation of base excision repair greatly increases cellular radiation sensitivity in model systems. Both low and higher LET radiation used in the treatment of a variety of cancers produces clustered DNA lesions which include the many damages recognized and removed during base excision repair of single lesions. During the prior funding period, we established that attempted but abortive repair of radiation-induced clustered DNA damages leads to an increase in the number of potentially lethal double strand breaks and an increase in cellular lethality. We also showed that this increase in the formation of double strand breaks and cellular lethality was mediated solely by the DNA glycosylases that recognize the initial base lesions. Thus, manipulation of the substrate specificities of the DNA glycosylases that recognize radiation damage could be used to potentiate DNA damage during radiotherapy and significantly influence treatment outcome and therapeutic gain. The overall goal of the proposed research is to delineate the substrate specificities of the DNA glycosylases that initiate base excision repair of radiation damage and as well produce potentially lethal double strand breaks at radiation-induced clustered lesions. The ultimate goal is to develop strategies based on structure/function relationships that would increase the effective dose to the tumor without damaging the normal tissue.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA033657-23A1
Application #
6826344
Study Section
Radiation Therapeutics and Biology Study Section (RTB)
Program Officer
Pelroy, Richard
Project Start
1982-04-01
Project End
2009-07-31
Budget Start
2004-08-20
Budget End
2005-07-31
Support Year
23
Fiscal Year
2004
Total Cost
$453,817
Indirect Cost
Name
University of Vermont & St Agric College
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
066811191
City
Burlington
State
VT
Country
United States
Zip Code
05405
Robey-Bond, Susan M; Benson, Meredith A; Barrantes-Reynolds, Ramiro et al. (2017) Probing the activity of NTHL1 orthologs by targeting conserved amino acid residues. DNA Repair (Amst) 53:43-51
Wallace, Susan S; Murphy, Drew L; Sweasy, Joann B (2012) Base excision repair and cancer. Cancer Lett 327:73-89
Faucher, Frederick; Wallace, Susan S; Doublie, Sylvie (2010) The C-terminal lysine of Ogg2 DNA glycosylases is a major molecular determinant for guanine/8-oxoguanine distinction. J Mol Biol 397:46-56
Faucher, Frédérick; Robey-Bond, Susan M; Wallace, Susan S et al. (2009) Structural characterization of Clostridium acetobutylicum 8-oxoguanine DNA glycosylase in its apo form and in complex with 8-oxodeoxyguanosine. J Mol Biol 387:669-79
Faucher, Frédérick; Wallace, Susan S; Doublié, Sylvie (2009) Structural basis for the lack of opposite base specificity of Clostridium acetobutylicum 8-oxoguanine DNA glycosylase. DNA Repair (Amst) 8:1283-9
Faucher, Frédérick; Duclos, Stéphanie; Bandaru, Viswanath et al. (2009) Crystal structures of two archaeal 8-oxoguanine DNA glycosylases provide structural insight into guanine/8-oxoguanine distinction. Structure 17:703-12
Robey-Bond, Susan M; Barrantes-Reynolds, Ramiro; Bond, Jeffrey P et al. (2008) Clostridium acetobutylicum 8-oxoguanine DNA glycosylase (Ogg) differs from eukaryotic Oggs with respect to opposite base discrimination. Biochemistry 47:7626-36
Bandaru, Viswanath; Blaisdell, Jeffrey O; Wallace, Susan S (2006) Oxidative DNA glycosylases: recipes from cloning to characterization. Methods Enzymol 408:15-33
Watanabe, Takashi; Blaisdell, Jeffrey O; Wallace, Susan S et al. (2005) Engineering functional changes in Escherichia coli endonuclease III based on phylogenetic and structural analyses. J Biol Chem 280:34378-84
Blaisdell, J O; Harrison, L; Wallace, S S (2001) Base excision repair processing of radiation-induced clustered DNA lesions. Radiat Prot Dosimetry 97:25-31

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