Dissertation
Transcription factor specificity protein 1 (Sp1) regulates the centrochromatin landscape and centromeric transcription during mitosis
Doctor of Philosophy (Ph.D.), Drexel University
Jul 2016
DOI:
https://doi.org/10.17918/etd-7146
Abstract
Chromosomal instability (CIN) is a dynamic and continual gain or loss of whole chromosomes, or parts of chromosomes, during cell division. It is associated with poor patient outcome in multiple cancer types, as well as tumor heterogeneity and resistance to multiple chemotherapeutics, underscoring its clinical importance. Despite its prevalence and clinical significance, the exact mechanisms that lead to CIN remain to be determined. The transcription factor Specificity Protein 1 (Sp1) regulates the transcription of genes involved with many cellular processes, including differentiation, cell cycle progression, DNA repair, apoptosis, and senescence. Sp1 binds to specific GC-rich elements through its highly conserved carboxy-terminal zinc finger DNA binding domain, and recruits various factors to chromatin to influence transcription. Our previous work shows that Sp1 is important for maintaining chromosomal stability during mitosis. We have shown that loss of Sp1 results in abnormal chromosome alignment along the metaphase plate, creation of micronuclei, and aneuploidy, as well as lagging chromosomes and anaphase bridges, all of which are phenotypes consistent with CIN. We now show that Sp1 localizes and binds to centromeres during mitosis. Rapid localization is dependent on ATM (ataxia telangiectasia mutated) activity, and does not require the Sp1 DNA binding domain. Loss of Sp1 results in disrupted centrochromatin, including changes in histone modifications and transcription of [alpha]-satellite arrays. Further, loss of Sp1 results in defects in centromeric cohesion, as well as a decrease in Centromeric Protein C (CENP-C) and Centromeric Protein A (CENP-A) binding at centromeres. These data suggest that Sp1 may be an important factor for maintaining the structure, function, and identity of centromeres, thereby maintaining chromosomal stability.
Metrics
35 File views/ downloads
29 Record Views
Details
- Title
- Transcription factor specificity protein 1 (Sp1) regulates the centrochromatin landscape and centromeric transcription during mitosis
- Creators
- Aislinn Rebecca Sowash Molinari - DU
- Contributors
- Jane Clifford (Advisor) - Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Biochemistry and Molecular Biology; College of Medicine; Drexel University
- Other Identifier
- 7146; 991014632415904721