In order for to maintain the genomic integrity of the organism,
individual cells within the organism must make appropriate life
and death decisions. Ongoing research is aimed at understanding
the molecular mechanisms by which cells respond to toxic chemicals
and radiation by activating pathways that lead to repair of damage
and cell recovery or to cell death by apoptosis or necrosis.
The information gained is used toward the design of therapeutic
strategies for the treatment of diseases in which cells are either
inappropriately resistant to cell death (cancer) or inappropriately
sensitive to cell death (heart attack, stroke, etc.). The
laboratory is studying the involvement of poly(ADP-ribose) polymerases
(PARPs) and poly(ADP-ribose) glycohydrolase (PARG) in the responses
of cells to potentially toxic conditions. PARPs and PARG
catalyze the opposing arms of ADP-ribose polymer cycles involved
in alternative responses to nuclear damage. These include
the repair of nuclear DNA and protein damage, pathways leading
to programmed cell death (apoptosis), and pathways leading to
cell death by necrosis. ADP-ribose polymer cycles are also
involved in the maintenance of the telomere structures that protect
the ends of chromosomes. The laboratory uses a structure-based
approach for characterization of its molecular targets.
Techniques routinely used in the laboratory include protein isolation
and microsequencing, cDNA cloning, heterologous protein expression
and characterization, site-directed mutagenesis, expression and
characterization of dominant negative proteins in cultured cells,
and the use of transgenic animals.
Wondrak, G.T., Varadarajan, S., Butterfield, D.A., and Jacobson,
M.K.: Formation of a protein bound pyrazinium free radical cation
during glycation of histone H1. Free Radical Biology & Medicine
29: 557-567, 2000.
Wondrak, G.T., Cervantes-Laurean, D., Jacobson, E.L., and Jacobson,
M.K.: Histone Carbonylation in vivo and in vitro. Biochemical
Journal 351: 769-777, 2000.
Jacobson, M.K., and Jacobson, E.L.: Discovering New ADP-ribose
Polymer Cycles: Protecting the Genome and More. Trends in Biochemical
Sciences:24, 415-417, 1999.
Amé , J.C., Jacobson, E.L., and Jacobson, M.K.: Molecular
Heterogeneity and Regulation of Poly(ADP-ribose) Glycohydrolase
Molecular and Cellular Biochemistry 193: 75-81, 1999.
Shieh, W.M., Amé , J.C., Wilson, M.V., Wang, Z.Q., Koh,
D.W., Jacobson, M.K., and Jacobson, E.L.: Poly(ADP-ribose) Polymerases
Null Mouse Cells Synthesize ADP-ribose Polymers. Journal of Biological
Chemistry 273: 30069-30072, 1998.
Lin, W.L., Amé, J.C., Aboul-Ela, N., Jacobson, E.L., and
Jacobson, M.K.: Isolation and Characterization of the cDNA Encoding
Bovine Poly(ADP-ribose) Glycohydrolase. Journal of Biological
Chemistry 272: 11895-11901, 1997.
