Protein quality control influencing DNA repair

DNA can be damaged in many different ways as a result of exogenous and endogenous forms of cellular stress. DNA damage usually induces the activation of DNA repair pathways and often a cell cycle arrest (a check point response). This reaction, referred to as the DNA-damage response (DDR), is typically initiated by proteins that recognize DNA lesions, and is followed by the recruitment and activation of proteins that trigger checkpoint signalling or directly perform the necessary repair steps. When repair is completed the machinery needs to be disassembled and the DDR turned off. Therefore, the DDR is a tightly controlled process, which is regulated at multiple levels.

Over the years, it became clear that DNA repair is fine-tuned by an enormous amount of DNA damage-induced posttranslational modifications. The main idea is that posttranslational modifications, including those of the ubiquitin family, lead to alterations in interactions between proteins that perform the necessary repair steps. DNA damage-induced posttranslational modifications thus induce the DNA repair protein complexes required to counteract the genomic insults to assemble.

However, other regulatory mechanisms are also active. The disassembly of DNA damage induced repair complexes must thus be highly orchestrated as well. In fact, there are indications that this is indeed the case. For example, upon binding to DNA lesions Rad23b dissociates from XPC (two proteins involved in nucleotide excision repair) in vivo3. This finding is surprising, as the formation of this complex is essential to initiate repair. Another example is how the chaperone-like segregase Cdc48/p97 separates the DNA-bound Rad51 and Rad52 complex – two essential recombination/DNA repair enzymes. These findings were especially important since they pointed out that dissociation of DNA repair complexes is not necessarily spontaneous but in fact regulated. Moreover, this regulation occurs at the DNA damaged site.

The disassembly/remodelling when the reaction is done or stalled are under-investigated and therefore barely understood. The direct need for more fundamental insight becomes urgent with for example the newest insights in the extreme genome instability in tumours. This instability is partly caused by the uncontrolled reactions of the various DNA repair pathways (e.g. homologous recombination and non-homologous end joining). Our aim is to investigate how DNA repair complexes are disassembled at the DNA.

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