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Dissertation
Phosphorylation of transcription factor Sp1 by the ATM pathway modulates the cellular response to DNA damage
Doctor of Philosophy (Ph.D.), Drexel University
Sep 2005
DOI:
https://doi.org/10.17918/00009064
Abstract
The human genome is constantly threatened by cytotoxic and mutagenic lesions that can lead to genomic instability, cancer and/or cell death. These lesions include small or bulky modifications to DNA bases and sugars, inter- and intra-strand crosslinks, as well as single- and double-strand breaks. In order to avoid cell death or neoplastic transformation generated by DNA damage, the cell has systems in place to sense, signal and repair this damage in a timely manner, ensuring that daughter cells do not inherit a dysfunctional genome. The PI3-related kinases ATM and ATR play a major role in transducing the DNA damage signal, targeting a variety of proteins to engage cell cycle checkpoints, facilitate DNA repair, and promote cell survival. Specificity Protein 1 (Sp1), an essential metazoan transcription factor involved in the regulation of a wide variety of cellular promoters including housekeeping and stress-inducible genes, is a target of this DNA damage response pathway in normal human fibroblasts. Sp1 is rapidly phosphorylated in response to DNA damaging agents such as hydrogen peroxide, ionizing radiation and ultraviolet radiation. This phosphorylation is mediated by the ATM/ATR kinases. We have identified that Sp1 is phosphorylated on serine-101, which is located within a cluster of ATM/ATR consensus SQ/TQ sites. The kinetics of Sp1 phosphorylation and dephosphorylation parallel those of H2AX, a marker of double strand breaks. Following the induction of DNA damage, Sp1 becomes more tightly associated with chromatin, with kinetics that coincide with Sp1 phosphorylation. While Sp1 forms foci in response to DNA damage, they do not co-localize with phospho-H2AX foci, suggesting that Sp1 is not at the DNA damage site. When cells are depleted of Sp1 by RNA interference, they become more sensitive to the cytotoxic effects of H₂O₂ or IR exposure. Together, these data place Sp1 in the DNA damage response pathway, and suggest that Sp1 may be involved in mediating cell survival following genotoxic stress.
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Details
- Title
- Phosphorylation of transcription factor Sp1 by the ATM pathway modulates the cellular response to DNA damage
- Creators
- Beatrix A. Olofsson
- Contributors
- Jane Clifford (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- x, 171 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 991021889085704721