Cellular Responses to Replication Problems
During every S-phase cells need to duplicate their genomes so that both daughter cells inherit complete copies of genetic information. It is a tremendous task, given the large sizes of mammalian genomes and the required precision of DNA replication. A major threat to the accuracy and efficiency of DNA synthesis is the presence of damaged DNA, e.g. abasic sites, single stranded DNA breaks, DNA crosslinks and adducts. This damage can be caused by exogenous agents, e.g. UV light, ionizing radiation, or environmental carcinogens, but is also an inevitable consequence of normal cellular metabolism. Replicative DNA polymerases, which carry out the bulk of DNA synthesis, evolved to do their job extremely precisely and effficiently. However, they are unable to use damaged DNA as templates, and, consequently, are stopped at most DNA lesions. Failure to restart such stalled forks can result in major chromosomal aberrations and lead to cell dysfunction or death. Therefore, a well-coordinated response to replication perturbation is essential for cell survival and wellbeing. It involves adjusting cell cycle progression to the emergency situation, and the use of specialized pathways promoting replication recovery. The aim of this thesis was to contribute to our understanding of the mechanisms the cell employs to deal with replication problems.
|Keywords||DNA, cellular metabolism, genomes|
|Promotor||Hoeijmakers, J.H.J. (Jan) , Kanaar, R. (Roland)|
|Publisher||Erasmus MC: University Medical Center Rotterdam|
Budzowska, M.. (2008, March 26). Cellular Responses to Replication Problems. Erasmus MC: University Medical Center Rotterdam. Retrieved from http://hdl.handle.net/1765/20412