Gilbert Chu, Ph.D.
Ph.D., M.I.T., 1973; M.D., Harvard, 1980.
Professor of Medicine (Oncology);
Professor of Biochemistry
Email:
Web: http://cmgm.stanford.edu/~chu/
Our laboratory effort has focused on the question of how cells recognize damaged DNA. We have identified and characterized proteins that bind specifically to damaged DNA and are studying their roles in the initial step of biochemical pathways for DNA repair, DNA recombination, and signaling cellular responses induced by DNA damage.
Xeroderma pigmentosum (XP) is an autosomal recessive disease characterized by defective nucleotide excision repair and a severe risk for skin cancer. We discovered a protein with UV-damaged DNA binding activity (UV-DDB) that is deficient in a subset of XP group E patients and recognizes UV-damaged DNA as well as a broad spectrum of bulky adducts. Expression of UV-DDB responds to p53, targets lesions for global genomic repair, and suppresses UV-induced mutagenesis without affecting UV survival. Further studies will define the importance of this pathway in carcinogenesis.
The Ku protein is a heterodimer of 70 kDa and 86 kDa that binds to DNA ends. We have shown that Ku will rescue X-ray sensitive mutant hamster cells that are deficient for double-strand break repair and V(D)J recombination. Ku is the DNA binding subunit of DNA-dependent protein kinase, which is activated by double-strand breaks. Structural and functional studies have focussed on how DNA activates the the kinase subunit to better understand a molecular mechanism for how DNA damage can be transduced into a phosphorylation signal.
We are also studying global cellular responses to ionizing and ultraviolet radiation in patients who have had adverse reactions to radiation therapy or early onset skin cancer. Our hope is that this research will shed light on the basic biochemical pathways that protect the genome from a broad spectrum of DNA damage and that progress will suggest new strategies for treating cancer.
We use microarrays to measure transcriptional responses in patient cells to ultraviolet and ionizing radiation. To determine the significance of changes in gene expression, we have developed a general method, Significance Analysis of Microarrays (SAM). Potential users can apply the method to their own data at the web site http://www-stat-class.stanford.edu/SAM/SAMServlet .
Select Publications (2003 - present)
Tibshirani R, Hastie T, Narasimhan B, Chu G (2003). Class prediction by nearest shrunken centroids, with applications to DNA microarrays. Statistical Sci 18:104-117.
Thorstenson Y, Roxas A, Kroiss R, Jenkins M, Yu K, Bachrich T, Muhr D, Wayne T, Chu G, Davis R, Wagner T, Oefner P (2003). Contributions of ATM mutations to hereditary breast and ovarian cancer. Cancer Res 63: 3325-3333.
Rieger K, Hong WJ, Tusher VG, Tang J, Tibshirani R, Chu G (2004).Toxicity from radiation therapy associated with abnormal transcriptional responses to DNA damage. Proc Natl Acad Sci USA 101: 6635-6640.
Rieger K, Chu G (2004). Portrait of transcriptional responses to ultraviolet and ionizing radiation in human cells. Nuc Acids Res 32(16): 4786-4803.
Budman J, Chu G (2005).Processing of DNA for nonhomologous end-joining by cell-free extract. EMBO J 24: 849-60.
Hong WJ, Warnke R, Chu G (2005). Immune Signatures in Follicular Lymphoma (Corres). N Engl J Med. 352: 1496-1497.
Last Updated: 2/23/06
