Uncovering novel and unexpected mechanisms for maintaining genome stability during DNA replication / Kevin D. Smith.
v, 146 p. : ill. (some col.) ; 29 cm.
- Medical subjects:
- Cell and Molecular Biology.
- Local subjects:
- Penn dissertations -- Cell and molecular biology.
Cell and molecular biology -- Penn dissertations.
- The maintenance of a complete, undamaged genome is essential for normal cellular function and an organism's overall ability to survive. Deficiencies in the processes responsible for maintaining genome stability are known to play important roles in many human malignancies, such as cancer and a number of heritable diseases and syndromes, and the process of aging. The genome is especially vulnerable to damage or alteration during DNA replication, and there are a number of mechanisms utilized by cells that function to monitor and protect the genome during this essential process. The studies herein describe how components involved in DNA replication interface with the DNA replication checkpoint, and how the cell responds to DNA damage caused by stress during DNA synthesis or ionizing radiation treatment on a genomic scale.
We have demonstrated that the Tim/Tipin complex is involved in regulating single-stranded DNA accumulation at replication forks during the process of DNA replication. Furthermore, we have shown that this important genome stabilizing mechanism functions upstream of the DNA replication checkpoint, which is mediated by two checkpoint regulatory proteins, ATR and Chk1. Finally, we utilize a genome-wide analysis to map the DNA damage response to stress during DNA replication and ionizing radiation treatment. By investigating regions of the genome that develop gammaH2AX, a marker for DNA damage in the form of DNA double-strand breaks, we have determined that specific regions of the genome are more prone to DNA damage signaling, and that these regions correlate with other DNA-related processes, i.e. gene density and DNA replication. Collectively, through these analyses we have advanced the understanding of how cells maintain genome stability during DNA synthesis and, have identified mechanisms that may be useful in developing future therapeutic treatments.
- Advisers: Eric J. Brown; Roger A. Greenberg.
Thesis (Ph.D. in Cell and Molecular Biology) -- University of Pennsylvania, 2011.
Includes bibliographical references.
- Brown, Eric J., advisor.
Greenberg, Roger A., advisor.
University of Pennsylvania.
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