Non-canonical ubiquitination in the response to DNA damage and DNA replication stress View Homepage


Ontology type: schema:MonetaryGrant     


Grant Info

YEARS

2016-2019

FUNDING AMOUNT

351780 CHF

ABSTRACT

Ubiquitination is a widely used signalling device that regulates almost all cellular processes. The versatility of ubiquitination is due to the fact that it can form eight different homotypic chains, depending on the Lys residue (K) involved in the linkage, in addition to various heterotypic chains. This variety of combinations increases the complexity of the ubiquitin (Ub) system, providing structural flexibility that results in a multitude of functional outcomes. Ub modifications have long been implicated in cell cycle control and replication, and more recently in the regulation of the cellular response to genotoxic lesions, a process known as “DNA Damage Response” or DDR. Although these pathways are mainly driven by canonical ubiquitination - i.e. K48 (degradative funtion) and K63 (protein-protein interaction) - we recently demonstrated that the atypical K27 linkage is essential to promote RNF168-mediated chromatin ubiquitination and to activate the DDR signalling cascade. Moreover, we obtained preliminary data suggesting that additional ubiquitination events, possibly including non-canonical Ub-linkages and yet-undefined RNF168 targets, are required for efficient DNA replication and to protect cells from genotoxic treatments interfering with DNA synthesis.The central goal of this research proposal is to expand our mechanistic understanding of the role of non-canonical ubiquitination in the maintenance of genome integrity. We will further characterize the role of K27-linkage in DDR, we will identify the ubiquitinating machinery responsible for this modification in vivo and new targets of RNF168, by employing a recently developed method to study protein-protein interactions. We will explore which types of Ub-linkages play a pivotal role to assist the replication process, especially in face of drug-induced replication stress. We will generate a Ub replacement system to further characterize the role of non-canonical ubiquitination in DDR and in replication. We will also assess the role in replication of the Ub ligase RNF168 and its known ubiquitination targets. These investigations will exploit a specialized technological platform available in two neighbouring labs of the same institution, with proven potential to increase mechanistic understanding of cancer-relevant molecular mechanisms of genome stability. By extending our comprehension of Ub modification in DDR and DNA replication, we aim to unveil key factors for the transactions assisting genome stability and to offer new promising targets to potentiate cancer chemotherapy. More... »

URL

http://p3.snf.ch/project-166370

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