The genome of living organisms is subject to a wide variety of damages caused spontaneously or by exposure to environmental agents, which interact with DNA. If unrepaired, DNA damage can result in permanent alterations in nucleotide sequence, thereby generating mutations. The potential phenotypic consequences of mutations in somatic cells include neoplastic transformation. My laboratory is interested in understanding the molecular mechanisms by which cells repair and tolerate DNA damage and thereby mitigate against the phenotypic consequences of mutational alterations.
The hereditary human diseases xeroderma pigmentosum (XP) and Cockayne’s syndrome (CS) are characterized by defective repair of DNA base damage. Each of these diseases is genetically complex. In the case of XP 10 distinct genes have been implicated and two genes have been implicated in CS. XP is characterized clinically by a profound susceptibility to skin cancer associated with sunlight exposure, while CS is characterized by severe post-natal developmental and neurological disorders. We have developed mouse models for XP and CS by targeted gene replacement. The predisposition of these mice to various carcinogens, as well as the molecular pathogenesis of cancer in these mouse models is under active investigation.
DNA damage tolerance involves the ability of cells to bypass sites of arrested DNA replication due to base damage. One of the known tolerance mechanisms. called translesion DNA synthesis (TLS), utilizes multiple specialized DNA polymerases to replicate past sites of base damage. The molecular biology and biochemical mechanism of TLS in mammalian cells is under study in the laboratory.
RESEARCH INTERESTS
DNA repair and Its relationship to carcinogenesis
RECENT PUBLICATIONS
Nahari, D., McDaniel, L., Task, L. B., Daniel, R. L., Velasco-Miguel, S. and Friedberg, E. C., "Mutations in the Trp53 Gene of UV-Irradiated Xpc Mutant Mice Suggest A Novel Xpc-Dependent DNA Repair Process" DNA Repair, 3:379-386, 2004
Friedberg, E. C., McDaniel, L. and Schultz, R. A., "The Role of Endogenous and Exogenous DNA Damage and Mutagenesis" Curr. Opin. Genet. Devel., 14:5-10, 2004
Guo, C., Fischhaber, P. L., Luk-Paszyc, M., Masuda, Y., Zhou, J., Kisker, K. and Friedberg. E. C., "Mouse Rev1 Protein Interacts With Multiple DNA Polymerases Involved in Translesion DNA Synthesis" EMBO J., 22:6621-6630, 2004
Friedberg, E. C. and Fischhaber, P.L., "DNA Replication Fidelity" Encyclopedia of the Human Genome, 2:167-171, 2003
SIGNIFICANT PUBLICATIONS
Friedberg, E. C., "How Nucleotide Excision Repair Protects Against Cancer" Nature Reviews Cancer, 1:22-33, 2001
Friedberg, E. C., "DNA Damage and Repair." Nature, 421:436-439, 2003
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