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The 78th Seminar

Orchestration of the DNA damage response by regulatory ubiquitylation

Dr. Simon Bekker-Jensen
Associate Professor, Novo Nordisk Foundation Center for Protein Research,
Copenhagen N, Denmark


DNA damage arises continuously as the result of intracellular metabolism and upon exposure to a multitude of genotoxic agents. If left unrepaired, such insults can be life-threatening for organisms as they alter the content and organization of the genetic material. To overcome this challenge to genomic stability, cells have evolved a global signaling network known as the DNA damage response that senses different types of genotoxic stress to mount a coordinated response, which includes modulation of cell cycle transitions and stimulation of DNA repair. Accordingly, the DNA damage response functions as a major cellular defence mechanism against the accumulation of genetic changes associated with diseases such as cancer. DNA double-strand breaks (DSBs) represent the most destructive type of chromosomal lesion and trigger rapid chromatin restructuring accompanied by accumulation of signalling and repair proteins in the vicinity of the DSB. These events are instrumental for restoring genomic integrity but the mechanisms behind protein retention on damaged chromosomes are not well understood at present. We have recently found that regulatory ubiquitylation of histones surrounding DSBs, mediated by the ubiquitin ligase RNF8, facilitates restoration of genome stability by licensing the DSB-modified chromatin to concentrate DNA repair factors near the lesions. In this presentation I will discuss our latest insights into the molecular mechanisms by which local, RNF8-mediated ubiquitylation promotes the DSB-induced chromatin response in human cells. In particular, we have identified additional ubiquitin ligases that cooperate with RNF8 to support DNA damage-dependent histone ubiquitylation and thereby generate permissive conditions for recruitment of DNA repair factors. These findings uncover novel layers of complexity in pathways that orchestrate protein interactions with sites of DNA damage and underscore the essential role of regulatory ubiquitylation in the protection of genome integrity.
 
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