Characterizing multiple roles for ubiquitination and SUMOylation in the DNA damage tolerance pathways
- Michelle Kathryn Zeman.
- Aug. 2013.
- Physical description
- online resource (xvi, 192 pages) : illustrations (some color)
- Zeman, Michelle Kathryn.
- Attardi, Laura. thesis advisor.
- Cimprich, Karlene. thesis advisor (primary).
- Villeneuve, Anne, 1959- thesis advisor.
- Wysocka, Joanna, Ph. D. thesis advisor.
- Stanford University. Program in Cancer Biology.
- Stanford University. Committee on Graduate Studies. degree grantor.
- Includes bibliographical references (p. 175-192). 195 refs.
- Accurate maintenance and transmission of DNA from one cell to another is crucial for the propagation of a species, as accumulation of random mutations can result in loss of critical cellular functions. During DNA replication, DNA lesions encountered by the replication machinery cannot be repaired, as unwinding of the parental DNA separates the damaged DNA from the undamaged template which would normally be used for repair. These replication-blocking lesions can be seriously detrimental to the cell, as stalled replication forks can collapse into double-stranded DNA breaks and lead to genomic rearrangements. To prevent the accumulation of stalled and collapsed forks, the cell uses DNA damage tolerance (DDT) pathways to bypass the DNA lesion and complete replication. There are two known DDT pathways -- translesion synthesis, which uses specialized translesion synthesis polymerases to replicate directly over a DNA lesion, and template switching, which promotes invasion into the sister chromatid and extrusion of the newly synthesized strand for use as a template. These processes rely on a series of E3 ubiquitin ligases in mammalian cells, including Rad18, SHPRH, and HLTF. As a result, we wished to examine the role of ubiquitin modification, and ubiquitin-related SUMO modification, on the control of DDT. Together, the data presented here provide important new insight into how cells control the response to DNA damage and, importantly, how this response is repressed in the absence of damage. As misregulation of Rad18 and SHPRH, as well as several other DDT components, has been implicated in cancer development and progression, knowing more about this regulation may help us understand how cells avoid the generation of mutations, and ultimately the development of disease.
- Publication date
- Submitted to the Cancer Biology Program and the Committee on Graduate Studies of Stanford University.
- Thesis (Ph.D.)--Stanford University, 2013.