Patricia Lynn Opresko
Associate Professor of Environmental and Occupational Health, University of Pittsburgh
Maintenance of the genome is critical for the survival and health of an organism. Genomic mutations and alterations promote cancer, and the incidence of cancer increases exponentially with age. The Opresko lab is investigating the mechanisms of genomic instability associated with aging and diseases related to aging. Telomeres are a region of the genome that profoundly influences life span, human disease and genome integrity. Human telomeres are protein-DNA structures that preserve chromosome ends and limit the replicative potential of somatic cells. Increased loss of telomeric DNA and telomere dysfunction has been observed in several diseases associated with aging, in progeroid disorders, and after oxidative stress.
The goals of the Opresko lab are to understand both the mechanisms of accelerated telomere loss and the cellular processes that preserve telomeric DNA. In order to visualize telomeres on human chromosomes we rely on fluorescent in situ hybridization techniques in which the telomeres are stained with a complementary peptide nucleic acid (PNA) probe. We are using complementary cellular biology and biochemical techniques to investigate the consequences of DNA damage on telomere structure and integrity, and the actions of proteins that protect and repair the telomeres. Currently, we are elucidating roles for the DNA repair protein WRN in preserving telomeres. Defects in the WRN protein causes the premature aging disorder Werner syndrome and accelerated loss of telomeric DNA. A better understanding of the unique vulnerability of telomeres to damage by environmental and endogenous genotoxic agents will be useful for advancing therapies that 1) preserve telomere function to maintain healthy cells after genotoxic stress, or that conversely 2) deplete telomeres to arrest proliferating cancer cells.
Adler, N.; Pantell, K.; O’Donovan, A.; Blackburn, E.; Cawthon, R.; Koster, A.; Opresko, P.; Newman, A.; Harris, T.B.; Epel, E. Educational attainment and late life telomere length in the Health, Aging and Body Composition Study. Bain Behav Immun. 2013, 27: 15-21.
Damerla, R.R.; Knickelein, K.E.; Strutt, S.; Liu, F.-J.; Wang, H.; Opresko, P.L. The Werner Syndrome protein suppresses the formation of large deletions during the replication of human telomeric repeats. Cell Cycle 2012, 11: 3036-44.
Hwang, H.; Buncher, N.; Opresko, P.L.; Myong, S. Telomeric tail dynamics and sliding clamp activity of POT1-TTP1. Structure 2012, 20: 1872-80.
Miller, A.S.; Balakrishnan, L.; Buncher, N.A.; Opresko, P.L*; Bambara, R.A*. Telomere proteins POT1, TRF1 and TRF2 Augment Long Patch Base Excision Repair In Vitro. Cell Cycle 2012, 11: 998-1007. * co-corresponding authors
Choi, S.; Wang, W.; Rebeiro, A.J.S.; Kalinowski, A.; Gregg, S.Q.; Opresko, P.L.; Niedernhofer, L.J.; Rohde G.K.; Dahl K.N. Computational image analysis of nuclear morphology associated with various nuclear-specific aging disorders. Nucleus 2011, 6: 570-9.
O’Donovan, A.; Pantell, M.S.; Puterman, E.; Dhabhar, F.S.; Blackburn, E.H.; Yaffe, K.; Cawthon, R.M.; Opresko, P.L.; Hsueh, W.C;, Satterfield, S.; Newman, A.B.; Ayonayon, H.N.; Rubin, S.M.; Harris, T.B.; Epel, E.S. Cumulative inflammatory load is associated with short leukocyte telomere length in the health, aging and body composition study. PLoS ONE 2011. 6: e19687
Sanders, J.L.; Iannaccone, A.; Boudreau, R.; Conley, Y.P.; Opresko, P.L.; Hsueh, W-C.; Cummings, S.R.; Cawthon, R.M.; Harris, T.B.; Nalls, M.A.; Kritchevsky, S.B.; Newman, A.B. The association of cataract with leukocyte telomere length in older adults: Defining a new marker of aging. J Gerontol A Biol Sci Med Sci 2011, 66A : 639-645.
Wang, H.; Nora, G.J.; Ghodke, H.; Opresko, P.L. Single Molecule Studies of Physiologically Relevant Telomeric Tails Reveals POT1 Mechanism for Promoting G-quadruplex Unfolding. J. Biological Chemistry 2011, 286: 7479-89.
Damerla, R.R.; Knickelbein, K.E.; Kepchia, D.; Jackson, A.; Armitage, B.A.; Eckert, K.A.; Opresko, P.L. Telomeric repeat mutagenicity in human somatic cells is modulated by repeat orientation and G-quadruplex stability, DNA Repair 2010, 9:1119-29.
Kusumoto-Matsuo, R.; Opresko, P.L.; Ramsden, D.; Tahara, H.; Bohr, V.A. Cooperation DNA-PKcs and WRN helicase in the maintenance of telomeric D-loops. Aging 2010. 2:274-84.
Liu, F.-J.; Barchowsky, A.; Opresko, P.L. The Werner Syndrome protein suppresses telomeric instability caused by chromium (VI) induced DNA replication stress. PLoS ONE 2010, 5:e11152.
Nora, G.; Buncher, A.; Opresko, P.L. Telomeric protein TRF2 protects Holliday junctions with telomeric arms from displacement by the Werner Syndrome helicase. Nucleic Acids Research 2010. 38: 3984-98.
Shah, S.; Opresko, P.; Xiao, M.; Lee, M.; Eckert, K. DNA structure and the Werner protein modulate human DNA polymerase delta-dependent replication dynamics within the common fragile site FRA16D. Nucleic Acids Research 2010. 38: 1149-62.