Determining the role and mechanism of action of the SUMO targeted ubiquitin ligase RNF4 in maintaining genome integrity. (360G-Wellcome-098391_Z_12_Z)
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.
Where is this data from?
This data was originally published by The Wellcome Trust. If you see something about your organisation or the funding it has received on this page that doesn't look right you can submit a grantee amendment request. You can hover over codes from standard codelists to see the user-friendly name provided by 360Giving.
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 |