| Laboratory of Molecular Gerontology |
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| Patricia J. Gearhart, Ph.D., Senior Investigator Section on Antibody Diversity |
 Dr. Patricia Gearhart received her Ph.D. in Immunology from the University of Pennsylvania in 1974. She obtained postdoctoral training at the Johns Hopkins University and was a staff associate at the Carnegie Institution of Washington until 1982. She then became a faculty member at the Johns Hopkins University until 1995, when she moved to her present position at the NIA.Research Interests: Somatic Hypermutation of Immunoglobulin Variable Genes: Somatic hypermutation of variable genes, which encode a portion of immunoglobulin molecules, occurs at a frequency that is a million times greater than mutation in other genes. The molecular mechanism that introduces these mutations is unknown. Our project has three aims. DNA Polymerases in Somatic Hypermutation of Immunoglobulin Variable Genes: Somatic hypermutation of variable genes, which encode a portion of immunoglobulin molecules, occurs at a frequency that is a million times greater than mutation in other genes. The molecular mechanism that introduces these mutations is unknown. Evidence points to a process that involves DNA repair events at sites of targeted strand breaks. In vertebrate cells, there are many recently identified DNA polymerases that inaccurately copy templates. One or more of these are potential candidates for enzymes that introduce base changes during hypermutation. We are studying the roles of DNA polymerases eta, and iota in the mechanism. |
| Polymerase eta is defective in people with xeroderma pigmentosum variant disease. We sequenced variable genes from three patients and found that their frequency of hypermutation was normal, but the types of base changes were different. Polymerase eta-deficient clones had a three-fold decrease in the proportion of mutations at A and T with a concomitant rise of mutations at G and C. It is notable that this shift in mutation pattern is consistent with the specificity of the polymerase when copying non-damaged DNA in vitro. This finding implies that polymerase eta is an A-T mutator in hypermutation, and another polymerase acts at G and C nucleotides. We are currently trying to identify proteins that interact with polymerase eta during hypermutation. |
| In collaboration with R. Woodgate, we have studied the specificity of polymerase iota on DNA substrates that might be formed during hypermutation. The overall fidelities of the polymerase are 10-fold lower when it fills a template at a DNA terminus compared to when it fills a longer template. However, the frequency and pattern of hypermutation in mice that are deficient for polymerase iota were similar to wildtype mice, suggesting that its participation in hypermutation is subtle, and other polmerases can compensate in its absence. |
| Contact Information: Laboratory of Molecular Gerontology Biomedical Research Center, room 06B127 251 Bayview Boulevard, Suite 100 Baltimore, MD 21224-6825 Phone 410-558-8561 Fax 410-558-8157 E mail gearharp@grc.nia.nih.gov For more information about the Laboratory: http://www.grc.nia.nih.gov/branches/lmg/lmg.htm |
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