This proposal focuses on DNA repair enzymes and signaling proteins with multiple roles in cellular responses to DNA damage. We view these multitasking proteins as potential control nodes that may integrate DNA damage-specific signals and marshal the appropriate repair process(es) to the sites of DNA damage. A frontier area in the field of DNA repair is to understand how the biochemical pathways of DNA repair are coordinated with one another, in a manner analogous to other intracellular signaling pathways. Our immediate efforts are focused on 1) defining the mechanism of substrate selection by mammalian DNA ligase III in DNA damage responses, 2) creating a """"""""chemical genetic switch"""""""" to shut off the NER pathway in order to explore other diverse functions of the repair endonuclease ERCC1-XPF, and 3) the enzymatic regulation of Sir2, a protein deacetylase with diverse activities, including DNA repair functions. We are using a structure-based approach to develop small molecule modulators of protein- protein interactions and enzymatic activities that can ultimately be used to probe the physical interactions and functional crosstalk between DNA repair pathways in living cells. Inhibitors of DNA repair activities may ultimately be useful in treating cancers that have become resistant to DNA crosslinkers, alkylating agents, and other DNA-targeted therapies.
We are studying how damaged DNA is repaired. These repair processes are essential for the normal maintenance of our genetic blueprint, but they can also cause resistance to anti-cancer drugs that kill tumors by inflicting damage to DNA. A better understanding of basic DNA repair mechanisms could lead to the development of drugs used to temporarily switch off repair during cancer chemotherapy.
|Pascal, John M; Ellenberger, Tom (2015) The rise and fall of poly(ADP-ribose): An enzymatic perspective. DNA Repair (Amst) 32:10-6|
|Kim, In-Kwon; Stegeman, Roderick A; Brosey, Chris A et al. (2015) A quantitative assay reveals ligand specificity of the DNA scaffold repair protein XRCC1 and efficient disassembly of complexes of XRCC1 and the poly(ADP-ribose) polymerase 1 by poly(ADP-ribose) glycohydrolase. J Biol Chem 290:3775-83|
|Della-Maria, Julie; Hegde, Muralidhar L; McNeill, Daniel R et al. (2012) The interaction between polynucleotide kinase phosphatase and the DNA repair protein XRCC1 is critical for repair of DNA alkylation damage and stable association at DNA damage sites. J Biol Chem 287:39233-44|
|Kim, In-Kwon; Kiefer, James R; Ho, Chris M W et al. (2012) Structure of mammalian poly(ADP-ribose) glycohydrolase reveals a flexible tyrosine clasp as a substrate-binding element. Nat Struct Mol Biol 19:653-6|
|Sperry, Justin B; Smith, Craig L; Caparon, Michael G et al. (2011) Mapping the protein-protein interface between a toxin and its cognate antitoxin from the bacterial pathogen Streptococcus pyogenes. Biochemistry 50:4038-45|
|Smith, Craig L; Ghosh, Joydeep; Elam, Jennifer Stine et al. (2011) Structural basis of Streptococcus pyogenes immunity to its NAD+ glycohydrolase toxin. Structure 19:192-202|
|Orelli, Barbara; McClendon, T Brooke; Tsodikov, Oleg V et al. (2010) The XPA-binding domain of ERCC1 is required for nucleotide excision repair but not other DNA repair pathways. J Biol Chem 285:3705-12|
|Cotner-Gohara, Elizabeth; Kim, In-Kwon; Hammel, Michal et al. (2010) Human DNA ligase III recognizes DNA ends by dynamic switching between two DNA-bound states. Biochemistry 49:6165-76|
|Perry, J Jefferson P; Cotner-Gohara, Elizabeth; Ellenberger, Tom et al. (2010) Structural dynamics in DNA damage signaling and repair. Curr Opin Struct Biol 20:283-94|
|Antony, Edwin; Tomko, Eric J; Xiao, Qi et al. (2009) Srs2 disassembles Rad51 filaments by a protein-protein interaction triggering ATP turnover and dissociation of Rad51 from DNA. Mol Cell 35:105-15|
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