Edward L. Loechler
Professor of Biology
PhD, Brandeis University, 1979
Areas of interest: molecular biology; mechanisms by which carcinogens cause mutations and cancer
Cancer-causing substances or “carcinogens” cause mutations, which makes sense, since tumor cells have mutations in key genes involved in growth control. Benzo[a]pyrene (B[a]P) is a potent mutagen-carcinogen in the "polycyclic aromatic hydrocarbon" class, which are ubiquitous environmental contaminants produced by incomplete combustion (e.g., in car exhaust, power plant emissions, cigarette smoke and charred foods). B[a]P is often the most important component of soot based on its prevalence and its potency. B[a]P reacts at N2-guanine to give “+BP” ([+ta]-B[a]P-N2-dG), which causes G->T mutations.
We investigate the DNA polymerases (DNAPs) involved in mutagenic and non-mutagenic bypass of +BP, which in human cells involves the Y-Family DNAPs eta and kappa, respectively, whose functional orthologs are DNAPs V and IV, respectively, in E. coli, which is our model system since we can probe mechanism readily.
DNAP IV inserts dCTP correctly opposite +BP in the non-mutagenic pathway, while DNAP V inserts dATP in the G->T mutagenic pathway. We are investigating the structural determinants that define how these related proteins have functional differences. For example, we have identified an opening on the minor groove side of Y-family DNAPs that is important. DNAPs in the IV/kappa-class have large openings, which accommodate adducts with bulk that protrudes into the minor groove (such as +BP) and, thus, allow accurate dCTP insertion. DNAPs in the V/eta-class have small openings, which do not properly accommodate adducts like +BP, and, thus, make misinsertions leading to mutations. Our ultimate goal is to define why Y-family DNAPs are accurate in some cases, but cause mutations relevant to cancer causation in other cases.
- BI216 Intensive Genetics
- BI118 Biology II (Honors Introductory Biology)
- BI 552 Molecular Biology I
- Seo KY, Lee D, Chandani S, Loechler EL. (Submitted). Y-Family DNA Polymerases IV and V of E. coli Are Involved in Both the Non-Mutagenic and G->T Mutagenic Pathway for the Major Adduct of Benzo[a]pyrene (N2-dG).
- Chandani S, Jacobs C, Loechler EL. (2010). Architecture of Y-Family DNA Polymerases Relevant to Translesion DNA Synthesis as Revealed in Structural and Molecular Modeling Studies. Journal of Nucleic Acids. pii: 784081.
- Chandani S, Loechler EL. (2010). Translesion Synthesis and Mutagenic Pathways in E. coli Cells. IN: The Chemical Biology of DNA Damage, Wiley-VCH, Weinheim, Germany, pp. 353-380.
- Chandani S, Loechler EL. (2009). Y-Family DNA Polymerases May Use Two Different dNTP Shapes for Insertion: A Hypothesis and Its Implications Journal of Molecular Graphics and Modelling. 27, 759 - 769.
- Seo K-Y, Yin J, Donthamsetti P, Chandani S, Lee CH, Loechler EL. (2009). Amino Acid Architecture that Influences dNTP Insertion Efficiency in Y-Family DNA Polymerase V of E. coli. Journal of Molecular Biology. 392, 270 - 282.
- Clapp RW, Jacobs MW, Loechler EL. (2008). Environmental and Occupational Causes of Cancer: New Evidence 2005 - 2007. Rev. Env. Health 23, 1-37.
- Chandani S, Lee CH, Loechler EL. (2007). Molecular Modeling Benzo[a]pyrene N2-dG Adducts in Two Partially Overlapping Active Sites of the Y-Family DNA Polymerase Dpo4. Journal of Molecular Graphics and Modelling. 25, 658-670.
- Seo K -Y, Nagalingam A, Miri S, Yin J, Kolbanovskiy A, Shastry A, Loechler EL. (2006). Mirror Image Stereoisomers of the Major Benzo[a]pyrene N2-dG Adduct Are Bypassed by Different Lesion-Bypass DNA Polymerases in E. coli DNA Repair 5, 515-527.