Determining the role and mechanism of action of the SUMO targeted ubiquitin ligase RNF4 in maintaining genome integrity. (360G-Wellcome-098391_Z_12_Z)

£1,922,744

RNF4 is a RING containing ubiquitin E3 ligase with specificity for polySUMO chains that is required for the therapeutic effect of arsenic trioxide in treatment of Acute Promyelocytic Leukaemia. Recently we established that RNF4 is required to maintain genome stability in higher eukaryotic cells. Our aim is to define the role of RNF4 in the DNA damage response and establish the molecular mechanism employed by RNF4, to catalyse transfer of ubiquitin to substrate. Our objectives are 1) to use quan titative proteomics to identify proteins that are selected as polySUMO modified substrates of RNF4 in response to DNA damage. 2) to establish how RNF4 recruitment leads to generation of a ubiquitin modification that is recognised by effector proteins that translate the ubiquitin signal into functional outputs. Importance of modifications will be determined by mutational analysis using in vivo readouts of DNA repair efficiency. Mechanisms by which RNF4 influences repair will be established using in vitro systems that recapitulate defined steps in repair. 3) Having recently proposed a model for the RING mediated transfer of ubiquitin to substrate we will test this using structural, biophysical and biochemical approaches and provide a description of the complex between ubiquitin loaded E2 and a dimeric RING ligase poised for catalysis. Ultimately our goal is to determine the structure of the complex containing polySUMO substrate, RNF4 E3 ligase and ubiquitin loaded E2. This would be a fir st in its class structure and would shed light on catalystic mechanisms employed by this important group of RING ligases.

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Grant Details

Amount Awarded 1922744
Applicant Surname Hay
Approval Committee Science Interview Panel
Award Date 2012-05-15T00:00:00+00:00
Financial Year 2011/12
Grant Programme: Title Investigator Award in Science
Internal ID 098391/Z/12/Z
Lead Applicant Prof Ronald Hay
Partnership Value 1922744
Planned Dates: End Date 2020-01-31T00:00:00+00:00
Planned Dates: Start Date 2012-10-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region Scotland