The integrity of DNA is crucial for the survival of living cells. However, DNA in cells is frequently damaged by both exogenous and endogenous agents. DNA lesions, on the other hand, are also essential steps in cellular process, such as DNA replication, recombination and conjugations. Both the accidental and programmed DNA damages have to be repaired efficiently and accurately; left un-repaired or mis-repaired, DNA damages lead to genome instability, resulting in oncogenous effects or even cell death. Among several major repair pathways, homologous recombination pathway precisely repairs the damaged DNA by searching and using a homologous DNA sequence in the genome as repairing template.
The bacterial RecA nucleoprotein filament formed on ssDNA at the broken DNA ends is the essential player during homologous recombination: it governs the homologous strand search, invasion and exchange. The formation and stability of the filament have to be tightly and precisely regulated by a set of accessory proteins and environmental co-factors; either insufficient or unlimited growth of the filament is lethal. However, the regulatory mechanisms of the filament by these accessory proteins remain elusive, partly due to lack of single-filament resolution studies.
Furthermore, force has been increasingly recognized as an important or even key determinant in diverse biological processes. Forces ubiquitously present on DNA, generated by molecular motors or condensation of topologically constrained DNA. Moreover, increasing evidences have suggested the existence of force on damaged DNA during homologous recombination. However, the potential regulatory role of force on homologous recombination have not been studied yet.
In this thesis work, I aim to understand the molecular mechanisms of dynamics and stability of RecA filament regulated by the accessory proteins and co-factors at single-filament level, and elucidate the role of mechanical force on these processes. (Abstract shortened by UMI.)
|School:||National University of Singapore (Singapore)|
|School Location:||Republic of Singapore|
|Source:||DAI-B 77/06(E), Dissertation Abstracts International|
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