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RESEARCH IN PROGRESS PRESENTATION

"Oxidative DNA Damage, DNA End Processing, and Human Disease"

October 3, 2005

Lawrence L. Povirk, PhD, and Professor, Department of Pharmacology and Toxicology, was the speaker for this week's Research in Progress Presentation. Dr. Povirk presented his topic, "Oxidative DNA Damage, DNA End Processing and Human Disease," to a an audience of clinical and research faculty and graduate students. His abstract on this topic follows:

DNA double-strand breaks induced by radiation, radiomimetic antitumor drugs and oxidative stress bear 3'-phosphoglycolate (PG) termini that must be removed to allow religation of the breaks. A survey of enzymes that might catalyze such removal has resulted in two primary candidates. Tyrosyl-DNA phosphodiesterase (TDP1) repairs topoisomerase I-mediated DNA damage but is also capable of converting 3'-PGs to 3'-phosphates, at least in vitro. TDP1 deficiency results in spinocerebellar ataxia with axonal neuropathy (SCAN1), and cells from SCAN1 patients are slightly radiosensitive, consistent with a role for TDP1 in PG removal. Artemis is a nuclease activated by DNA-dependent protein kinase that opens hairpin DNA ends during V(D)J recombination, but also shortens long 3' overhangs of double-strand breaks. In addition, Artemis can remove a single terminal 3'-PG nucleotide from short 3' overhangs. Artemis deficiency results in severe combined immune deficiency (SCID) as well as radiosensitivity. Thus, both biochemical and cellular data are consistent with a role for both TDP1 and Artemis in PG removal from double-strand breaks, and they may serve this function redundantly. A method of determining kinetics of PG removal from double-strand breaks in intact cells is being developed to assess the relative importance of each enzyme in PG removal.

For a printable version of this Research in Progress presentation, click here.

For more information visit the Department of Pharmacology and Toxicology Laboratory web page or contact Lawrence L. Povirk..

For more information about VCU Pathology Research in Progress presentations contact
 Dr. Lynne Elmore at (804) 628-0256; lwelmore@hsc.vcu.edu

Updated October 6, 2005