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The Role of PKA in the DNA Damage Checkpoint

Searle, Jennifer
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1123003066

Abstract Details

2005, PhD, University of Cincinnati, Medicine : Molecular Genetics, Biochemistry, and Microbiology.
Checkpoint proteins block progression through the cell cycle in order to prevent cell division when a cell has damaged or incompletely replicated DNA. This dissertation will focus on the DNA damage checkpoint signal transduction pathways which prevent mitotic progression following DNA damage. Mutations in the genes that encode for checkpoint proteins can lead to genomic instability, uncontrolled cell growth and cancer. Checkpoint proteins are being considered as drug targets for treatment of cancers, based on the hypothesis that the inactivation of a checkpoint protein enhances the rate at which cells fail to stop division with damaged DNA, which leads to accumulation of damaged DNA, and increases the probability of death for the cancer cell. Therefore, identifying novel checkpoint proteins could lead to the identification of new drug targets. The checkpoint pathways are conserved in the genetically amenable Saccharomyces cerevisiae, making it a good model system in which to identify novel proteins involved in regulating mitosis. The conserved checkpoint kinases Chk1 and Rad53 prevent mitotic progression by blocking the degradation of the securin, Pds1, thus preventing separation of the sister chromatids, and by inhibiting activation of the mitotic exit network (MEN), respectively. Chk1 and Rad53 play supporting roles in preventing mitosis following DNA damage. Although Chk1 prevents the degradation of Pds1 following DNA damage, Pds1 is degraded faster in cells containing a mutation in an upstream checkpoint kinase than in a chk1 mutant, suggesting that another pathway can regulate the destruction of Pds1. We show that the cAMP dependent protein kinase (PKA) pathway has a supporting role to Chk1 in preventing the degradation of the mitotic inhibitors Pds1 and Clb2 via regulation of the mitotic inducer Cdc20. We also found that proteins that regulated the levels of cAMP, and the checkpoint dependent phosphorylation of the PKA regulatory subunit were required to support the DNA damage checkpoint in blocking mitotic progression. These results suggested that there is cross-talk between the DNA damage checkpoint and PKA pathways, and that the DNA damage checkpoint may recruit the PKA pathway to reinforce the mitotic block following DNA damage.
Yolanda Sanchez (Advisor)
120 p.
DNA damage; cAMP dependent protien kinase; PKA; Cdc20; Pds1; Chk1

Recommended Citations

Citations

  • Searle, J. (2005). The Role of PKA in the DNA Damage Checkpoint [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1123003066

    APA Style (7th edition)

  • Searle, Jennifer. The Role of PKA in the DNA Damage Checkpoint. 2005. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1123003066.

    MLA Style (8th edition)

  • Searle, Jennifer. "The Role of PKA in the DNA Damage Checkpoint." Doctoral dissertation, University of Cincinnati, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1123003066

    Chicago Manual of Style (17th edition)

ucin1123003066
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© 2005, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.
Release 3.2.12