This thesis addresses the repair of DNA double-strand breaks (DSBs) that arise in different contexts, both artificially inflicted DNA damage and spontaneously arising breaks. We have found that the... Show moreThis thesis addresses the repair of DNA double-strand breaks (DSBs) that arise in different contexts, both artificially inflicted DNA damage and spontaneously arising breaks. We have found that the (mutational) repair outcome of a DSB depends on the context in which it occurs. When cells are not replicating, DSBs are repaired via non-homologous end-joining (NHEJ). NHEJ efficiency can be affected by defective RNA processing. In replicating cells, the preferable mechanism for DSB repair is homologous recombination (HR). When canonical HR cannot be executed, because the repair template is not available (at G4-induced breaks, for example) or when not all HR factors are present (in BRCA1 deficient situations), alternative annealing is needed. This is carried out via polymerase theta-mediated end-joining (TMEJ), or when homologous nucleotides are available, via HELQ-1 mediated annealing of these homologous stretches. Finally, we have found that large tandem duplications can arise when break ends cannot anneal properly after the extension step in HR. Show less
DNA is arguably the most important molecule found in any organism, as it contains all information to perform cellular functions and enables continuity of species. It is continuously exposed... Show more DNA is arguably the most important molecule found in any organism, as it contains all information to perform cellular functions and enables continuity of species. It is continuously exposed to DNA-damaging agents both from endogenous and exogenous sources. To protect DNA against these sources of DNA damage various DNA-repair mechanisms have evolved. If not properly repaired, DNA damage can lead to mutations that may eventually lead to cell-death or tumorigenesis. One of the most dangerous types of DNA damage is a DNA double-stranded break (DSB), in which a DNA molecule is broken into two pieces. Cells are equipped with several DSB-repair mechanisms to deal with this type of damage. Some of these mechanisms repair DSBs in an error-free fashion, while others are error-prone and can lead to the accumulation of mutations. Although accumulating many mutations in cells can lead to severely reduced cellular fitness, perfect DNA repair is less desirable in the long term as mutations allow for speciation and evolution to take place. The key question addressed in my thesis is which DSB-repair mechanisms organisms use to protect their genome against DSBs and I find alternative end-joining of DNA breaks to play a major role in maintaining genome stability. Show less
Bourguignon, M.; Foray, N.; Colin, C.; Pauwels, E. 2012
