Comparative and Functional Genomics Analysis of Superfund Toxicants

Summary

This Research Project led by Dr. Paul Russell, will use functional toxicogenomics and proteomics technologies to uncover the genes and pathways that determine cellular responses and genetic susceptibilities to arsenic, cadmium, chromium, nickel and other heavy metals that contaminate Superfund sites. Comparative functional genomics will provide key insights into some of the basic mechanisms that determine resistance or sensitivity to heavy metal toxicants. These studies are divided into three Specific Aims: 1) Assemble a functional genomic profile of fission yeast using a panel of environmental toxicants assessed with haploid and diploid deletion libraries. Barcode analysis determined by deep sequencing will provide a detailed and quantitative picture of the genes that determine susceptibilities to heavy metals. Cluster analysis will be applied to toxicants tested in pure forms or in mixtures. 2) Build on the functional genomic profiling data by assembling epistatic miniarray profiles (E-MAPs). These mutant interaction studies will define the genetic networks that determine cellular sensitivities to heavy metals and may uncover interactions with other pathways such as DNA damage responses (DDRs). The existence of conserved genetic interactions in human cells will be assessed by RNAi analyses. 3) Investigate changes in protein abundance triggered by heavy metal exposure using isobaric tag for relative and absolute quantitation (iTRAQ). These proteomic studies will provide further insights into how stress-regulated transcription factors and stress-activated protein kinases control cellular responses to heavy metal stress.

Publication

PubMed Central ID: 

Mejia-Ramirez, E., Limbo, O., Langerak, P., Russell, P. (2015) Critical Function of γH2A in S-Phase. PLoS Genet. 11(9), e1005517.

PubMedID: 26368543
PubMed Central ID: 

Sánchez, A., Roguev, A., Krogan, N.J., Russell, P. (2015) Genetic Interaction Landscape Reveals Critical Requirements for Schizosaccharomyces pombe Brc1 in DNA Damage Response Mutants. G3 (Bethesda). 5(5), 953-62.

PubMedID: 25795664
PubMed Central ID: 

Wang, L., Limbo, O., Fei, J., Chen, L., Kim, B., Luo, J., Chong, J., Conaway, R. C., Conaway, J. W., Ranish, J. A., Kadonaga, J. T., Russell, P., Wang, D. (2014) Regulation of the Rhp26ERCC6/CSB chromatin remodeler by a novel conserved leucine latch motif.  Proc Natl Acad Sci U S A111(52), 18566-71.

PubMedID: 25512493
PubMed Central ID: 

Guo, L., Ghassemian, M., Komives, E. A., Russell, P. (2012) Cadmium-induced proteome remodeling regulated by Spc1/Sty1 and Zip1 in fission yeast. Toxicol Sci. 129(1), 200-12.

PubMedID: 22610605
PubMed Central ID: 

Mendoza-Cozatl, D., Zhai, Z., Jobe, T., G.Z., A., Song, W. Y., Limbo, O., Russell, M., Kozlovskyy, V., Martinoia, E., Vatamaniuk, O. K., Russell, P., Schroeder, J. I. (2010) Tonoplast-localized Abc2 transporter mediates phytochelatin accumulation in vacuoles and confers cadmium tolerance. J Biol Chem. 285, 40416-40426.

PubMedID: 20937798
PubMed Central ID: 

Vashisht, A. A., Kennedy, P. J., Russell, P. (2009) Centaurin-like protein Cnt5 contributes to arsenic and cadmium resistance in fission yeast. FEMS. Yeast Res. 9, 257-269.

PubMedID: 19076239
PubMed Central ID: 

Rodríguez-Gabriel, M. A., Russell, P. (2008) Control of mRNA stability by SAPKs. Top Curr Genet. 20, 159-170.

PubMedID: 21738496
PubMed Central ID: 

Kennedy, P. J., Vashisht, A. A., Hoe, K. L., Kim, D. U., Park, H. O., Hayles, J., Russell, P. A. (2008) genome-wide screen of genes involved in cadmium tolerance in Schizosaccharomyces pombe. Toxicol Sci. 106(1), 124-39.

PubMedID: 18684775
PubMed Central ID: 

Rodriguez-Gabriel, M. A., Russell, P. (2008) Control of mRNA stability by SAPKs. Topics Curr Genet. 20, 50-166.

PubMedID: 14633985
PubMed Central ID: 

Rodríguez-Gabriel, M. A., Watt, S., Bähler, J., Russell, P. (2006) Upf1, an RNA helicase required for nonsense-mediated mRNA decay, modulates the transcriptional response to oxidative stress in fission yeast. Mol Cell Biol. 26, 6347-6356.

PubMedID: 16914721
PubMed Central ID: 

Rodriguez-Gabriel, M. A., Russell, P. (2005) Distinct signaling pathways respond to arsenite and reactive oxygen species in Schizosaccharomyces pombe. Eukaryotic Cell. 4(8), 1396-1402.

PubMedID: 16087744

Main Contact Information

Project Leader

  • Dr. Paul Russel       

Superfund Related Project Members

  • Leslie Madden, Administrator
  • Abantika Ganguly, Post-Doctoral Scholar
  • Arancha Sanchez, Post-Doctoral Scholar
  • Oliver Limbo, Research Technician

Resoucres

The Russell Lab

The Scripps Research Insitiute (TSRI) - Dr. Paul Russell

Other Publications

References From PubMed (NCBI)

Paul Russell, Ph.D.
Professor - Department of Cell and Molecular Biology
prussell@scripps.edu

Leslie Madden
Sr. Admininistrative Assistant
lmadden@scripps.edu

Mailing Address:
The Scripps Research Institute (TSRI)
10550 N. Torrey Pines Road, MB3
La Jolla, CA  92037 - USA

Contact

UCSD Superfund Research Center
University of California, San Diego
Pharmacology Department
9500 Gilman Drive, Mail Code 0722
La Jolla, CA 92093-0722