Our laboratory focuses on understanding how cells respond to DNA damage. Our research currently involves three areas that interact with each other: repair of ionizing radiation damage, repair of ultraviolet radiation damage, and transcriptional responses to DNA damage in cancer patients.

To understand how DNA damaged by ultraviolet radiation is recognized and targeted for nucleotide excision repair, we identified and characterized UV-damaged DNA binding activity (UV-DDB). We have shown that p48, one of the subunits of UV-DDB, is mutated in xeroderma pigmentosum group E patients. The p48 gene is transcriptionally activated after DNA damage by p53. This activation leads to an increase in global genomic repair and the suppression of UV-induced mutagenesis. Further studies are aimed toward defining how UV-DDB mediates global genomic repair.

To understand how DNA damaged by ionizing radiation is repaired, we have characterized the roles of Ku and DNA-dependent protein kinase (DNA-PK) in the repair of double-strand breaks produced by ionizing radiation or V(D)J recombination. Ku binds to DNA ends and recruits DNA-PK to the site. We determined the structural features on the damaged DNA required for the activation of DNA-PK. This has led to a model for kinase activation based on the electron crystallography structure of DNA-PK. Further studies in cell extracts will determine how the DNA ends are brought together, processed, and rejoined.

We have used microarrays to study the transcriptional response to ionizing radiation in lymphoblastoid cells from cancer patients with adverse reactions to radiation therapy. To interpret the microarray data, we invented new methods to analyze microarray data, including SAM (Significance Analysis of Microarrays). We successfully identified genes whose transcriptional responses predict risk for radiation toxicity. These results provide hope that treatment toxicity will soon be predicted by clinical tests.

• Budman J, Kim SA, Chu G "Processing of DNA for nonhomologous end-joining is controlled by kinase activity and XRCC4/LigaseIV." J Biol Chem 2007; More
• Tsai CJ, Kim SA, Chu G "Cernunnos/XLF promotes the ligation of mismatched and noncohesive DNA ends." Proc Natl Acad Sci U S A 2007; 104: 19: 7851-6 More
• Budman J, Chu G "Processing of DNA for nonhomologous end-joining by cell-free extract." EMBO J 2005; 24: 4: 849-60 More
• Rieger KE, Hong WJ, Tusher VG, Tang J, Tibshirani R, Chu G "Toxicity from radiation therapy associated with abnormal transcriptional responses to DNA damage." Proc Natl Acad Sci U S A 2004; 101: 17: 6635-40 More
• DeFazio LG, Stansel RM, Griffith JD, Chu G "Synapsis of DNA ends by DNA-dependent protein kinase." EMBO J 2002; 21: 12: 3192-200 More