Lawrence Sowers, PhDEmail: lsowers@llu.edu
The Sowers research group investigates the mechanisms of DNA damage and the cellular processes that repair damaged DNA. The DNA of all organisms is constantly under attack by both endogenous and exogenous agents resulting in 104 to 105 lesions in each cell per day. If unrepaired, these lesions can miscode (mutagenic effects) or alter the specificity of DNA-protein interactions (epigenetic effects). Both mutational events and epigenetic perturbations resulting from DNA damage have been identified in human cancer. Some research projects within the Sowers laboratory examine oxidation products that result from radiation, carcinogen exposure, and endogenous DNA damage including the pyrimidines 5-hydroxymethyluracil (HmU), 5-formyluracil (FoU), 5-hydroxymethylcytosine (HmC), 5-hydroxyuracil (HoU), and 5-hydroxycytosine (HoC). In addition, the Sowers group is investigating the consequences that oxidative halogenation of cytosine bases within DNA have on the methyltransferases which methylate DNA and the methyl-binding proteins instrumental in modifying gene expression. Other projects examine potential chemotherapy agents such as the nucleoside analogue, 5-aza-2'-deoxycytidine (DAC) which are incorporated into the DNA of replicating cells and represent an intentional DNA lesion. In DNA, DAC and other inhibitors of cytosine methyltransferase perturb the methylation of DNA leading to changes in gene expression. While many of the 109 bases of DNA are damaged each day, human cells have many enzymes which recognize and repair chemical lesions. The Sowers group examines the ability of these repair enzymes to remove lesions using a host of powerful techniques including computational methods, mass spectrometry, and nuclear magnetic resonance (NMR). The results and findings of the Sowers group should suggest how our environment can damage DNA, how to reduce DNA damage, particularly damage poorly repaired by human enzymes, and how to improve the effectiveness of chemotherapy drugs.
Valinluck V, Wu W, Liu P, Neidigh JW, Sowers LC. Impact of cytosine 5-halogens on the interaction of DNA with restriction endonucleases and methyltransferase. Chem Res Toxicol. 2006 Apr;19(4):556-62.
Valinluck V, Liu P, Kang JI Jr, Burdzy A, Sowers LC. 5-halogenated pyrimidine lesions within a CpG sequence context mimic 5-methylcytosine by enhancing the binding of the methyl-CpG-binding domain of methyl-CpG-binding protein 2 (MeCP2). Nucleic Acids Res. 2005 May 25;33(9):3057-64.
Kang JI Jr, Burdzy A, Liu P, Sowers LC. Synthesis and characterization of oligonucleotides containing 5-chlorocytosine. Chem Res Toxicol. 2004 Sep;17(9):1236-44.
Liu P, Burdzy A, Sowers LC. DNA ligases ensure fidelity by interrogating minor groove contacts. Nucleic Acids Res. 2004 Aug 24;32(15):4503-11.
Valinluck V, Tsai HH, Rogstad DK, Burdzy A, Bird A, Sowers LC. Oxidative damage to methyl-CpG sequences inhibits the binding of the methyl-CpG binding domain (MBD) of methyl-CpG binding protein 2 (MeCP2). Nucleic Acids Res. 2004 Aug 9;32(14):4100-8.
Rogstad DK, Heo J, Vaidehi N, Goddard WA 3rd, Burdzy A, Sowers LC. 5-Formyluracil-induced perturbations of DNA function. Biochemistry. 2004 May 18;43(19):5688-97.
Rogstad KN, Jang YH, Sowers LC, Goddard WA 3rd. First principles calculations of the pKa values and tautomers of isoguanine and xanthine.
Chem Res Toxicol. 2003 Nov;16(11):1455-62.
Liu P, Burdzy A, Sowers LC. Repair of the mutagenic DNA oxidation product, 5-formyluracil. DNA Repair (Amst). 2003 Feb 3;2(2):199-210.
Valinluck V, Liu P, Burdzy A, Ryu J, Sowers LC. Influence of local duplex stability and N6-methyladenine on uracil recognition by mismatch-specific uracil-DNA glycosylase (Mug). Chem Res Toxicol. 2002 Dec;15(12):1595-601.
Burdzy A, Noyes KT, Valinluck V, Sowers LC. Synthesis of stable-isotope enriched 5-methylpyrimidines and their use as probes of base reactivity in DNA. Nucleic Acids Res. 2002 Sep 15;30(18):4068-74.
Jang YH,
Liu P, Burdzy A, Sowers LC. Substrate recognition by a family of uracil-DNA glycosylases: UNG, MUG, and TDG. Chem Res Toxicol. 2002 Aug;15(8):1001-9.
Rogstad DK, Liu P, Burdzy A, Lin SS, Sowers LC. Endogenous DNA lesions can inhibit the binding of the AP-1 (c-Jun) transcription factor.
Biochemistry. 2002 Jun 25;41(25):8093-102.
Boulard Y, Fazakerley GV, Sowers LC. The solution structure of an oligonucleotide duplex containing a 2'-deoxyadenosine-3-(2-hydroxyethyl)- 2'-deoxyuridine base pair determined by NMR and molecular dynamics studies. Nucleic Acids Res. 2002 Mar 15;30(6):1371-8.
Baker D, Liu P, Burdzy A, Sowers LC. Characterization of the substrate specificity of a human 5-hydroxymethyluracil glycosylase activity.
Chem Res Toxicol. 2002 Jan;15(1):33-9.
Rusmintratip V, Sowers LC. An unexpectedly high excision capacity for mispaired 5-hydroxymethyluracil in human cell extracts.
Proc Natl Acad Sci U S A. 2000 Dec 19;97(26):14183-7.
Rusmintratip V, Riggs AD, Sowers LC. Examination of the DNA substrate selectivity of DNA cytosine methyltransferases using mass tagging. Nucleic Acids Res. 2000 Sep 15;28(18):3594-9.
La Francois CJ, Jang YH, Cagin T,
Sowers LC, Boulard Y, Fazakerley GV. Multiple structures for the 2-aminopurine-cytosine mispair. Biochemistry. 2000 Jun 27;39(25):7613-20.
Sowers LC. 15N-enriched 5-fluorocytosine as a probe for examining unusual DNA structures. J Biomol Struct Dyn. 2000 Feb;17(4):713-23.
Last Revised: Wed, Jun 28, 2006
