Gilbert Chu
Web: No lab page.
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. These issues are important for understanding carcinogenesis, since most cancers arise from mutations incorporated into the DNA during the replication of damaged DNA.
Xeroderma pigmentosum (XP) is an autosomal recessive disease characterized by defective nucleotide excision repair and a severe predisposition to skin cancer. We have discovered a protein, XPE binding factor (XPE-BF), that is deficient in a subset of XP group E patients, recognizes a broad spectrum of bulky adducts, and appears to be involved in a recognition step for nucleotide excision repair. We have recently discovered that the expression of this protein is regulated by p53 and plays a role in targeting lesions for global genomic repair.
The Ku protein was first identified as the autoantigen in patients with the autoimmune disease, scleroderma-polymyositis overlap syndrome. It is a heterodimer of 70 kDa and 86 kDa that binds to DNA ends, nicks, and gaps. We have discovered that Ku is deficient in X-ray sensitive mutant hamster cells that are deficient for both double-strand break repair and V(D)J recombination. The cDNA for the 86 kDa subunit of Ku confers X-ray resistance and V(D)J recombination activity to the mutant cells. Since Ku is also a component of a DNA-dependent protein kinase, it appears to play a role in a signaling pathway activated by DNA damage.
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.
Chu G, Chang E (1988) Xeroderma pigmentosum group E cells lack a nuclear factor that binds to damaged DNA. Science 242: 564-567.
Hwang B, Chu G (1993) Purification and characterization of a human protein that binds to damaged DNA. Biochemistry 32: 1657-1666.
Rathmell WK, Chu G (1994) A DNA-end-binding factor involved in double-strand break repair and V(D)J recombination. Mol. Cell .Biol. 14: 4741-4748.
Smider V, Rathmell WK, Lieber M, Chu G (1994) Restoration of X-ray resistance and V(D)J recombination in mutant cells by Ku cDNA. Science 266: 288-291.
Hwang BJ, Liao J, Chu G (1996) Isolation of a cDNA encoding a UV-damaged DNA binding factor defective in xeroderma pigmentosum group E cells. Mutation Res 362: 105-117.
Hammarsten O, Chu G (1998) DNA-dependent protein kinase: DNA binding and activation in the absence of Ku. Proc Natl Acad Sci USA 95: 525-530.
Hwang BJ, Toering S, Francke U, Chu G (1998) p48 activates UV-damaged DNA binding factor and is mutated in xeroderma pigmentosum group E. Mol Cell Biol 18: 4391-4399.
Smider V, Rathmell WK, Brown G, Lewis S, Chu G (1998) Failure of hairpin-ended and nicked DNA to activate DNA-dependent protein kinase: implications for V(D)J recombination. Mol Cell Biol 18: 6853-6858.
