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Serine ADP-ribosylation in genome stability and human disease (360G-Wellcome-210634_Z_18_Z)

ADP-ribosylation (ADPr) is a post-translational modification (PTM) of proteins, synthesised by the poly(ADP-ribose) polymerase (PARP) family of enzymes. Through the modification of a variety of mediator/effector proteins, PARPs control cellular processes that are critical for genome stability, including DNA repair, regulation of chromatin structure, transcription, apoptosis and mitosis. However, the proteins involved in these pathways and their mechanisms of regulation remain poorly understood. Recently, we identified ADPr on serine residues in proteins (Ser-ADPr) as a previously unknown PTM. We showed that Ser-ADPr synthesis is dependent on histone PARylation factor 1 (HPF1), a recently identified specificity factor and interactor of DNA repair PARPs - PARP1 and PARP2. We further showed that Ser-ADPr specifically targets proteins involved in the maintenance of genome stability. Finally, we also revealed that a hydrolase called ARH3 acts as specific enzyme for a timely reversal of Ser-ADPr. Our first goal of this project is to use biochemical and structural approaches to understand the exact molecular mechanism by which HPF1 and ARH3 work in the synthesis/removal of Ser-ADPr. Our second goal is to define the physiological processes controlled by Ser-ADPr and to understand how these processes are regulated in cells, using cell biology approaches and animal models.

£2,074,702

10 Apr 2018

Grant details
Amount Awarded 2074702
Applicant Surname Ahel
Approval Committee Science Interview Panel
Award Date 2018-04-10T00:00:00+00:00
Financial Year 2017/18
Grant Programme: Title Senior Research Fellowship Basic Renewal
Internal ID 210634/Z/18/Z
Lead Applicant Dr Ivan Ahel
Planned Dates: End Date 2023-10-01T00:00:00+00:00
Planned Dates: Start Date 2018-10-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region South East
Sponsor(s) Prof Matthew Freeman
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