PARPin · Regulation of (ADP-ribosyl)ation signalling in the DNA damage response: elucidating the function of a novel PARP1/ARTD1 interactor
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2016-03-01 → 2018-02-28
- EU contribution
- €183,455
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Regulation of (ADP-ribosyl)ation signalling in the DNA damage response: elucidating the function of a novel PARP1/ARTD1 interactor
The integrity of our DNA is constantly challenged by various types and sources of damaging agents that can cause genome instability, which is a common hallmark of many different cancer types and human pathologies. To protect DNA from damage, organisms have evolved a cellular defence mechanism termed the DNA damage response (DDR). The DDR includes a diverse set of molecular machines called proteins that act to sense DNA lesions and effectively repair the damage, restoring the health of the genetic code. Defects in the DDR can cause, or contribute to, a range of pathologies, including cancer, ageing, immune deficiencies and neurological disorders. As such, deepening our understanding of the DDR is of fundamental importance. To improve our understanding of the DDR, we need to discover all the factors that make up this cellular defence mechanism. More importantly, we need to discover the function of each of these factors and how they interact or ‘talk’ with other repair factors to ensure genome stability. Expanding our understanding of the DDR will lead to better targeted therapies for cancer and other DDR-related pathologies. In this project, the main objective was to characterise a novel factor involved in the DDR, to begin to understand how this factor regulates genome stability. Through this, our aim was to better understand the function of the clinically-relevant DNA repair enzyme PARP-1. In response to DNA damage, PARP-1 creates an SOS signal at DNA breaks called poly(ADP-ribosylation). In response to this SOS signal, repair proteins are mobilised to the DNA break to help with the process of repair. Therefore, PARP-1 plays a critical role in DNA repair by initiating the SOS signal. In other words, the research objective was to understand how PARP-1 is able to make the SOS signal in response to DNA breaks. Importantly, inhibiting this SOS signal with PARP inhibitors selectively kills certain cancer types, including breast and ovarian cancers, emphasising the clinical importance of the research objective.
Data: CORDIS, © European Union
Project objective
(ADP-ribosyl)ation is a dynamic post-translational modification synthesised by PARPs/ARTDs and regulates a diverse array of cellular processes, including the DNA damage response (DDR). The last decade has significantly improved our understanding of the key enzymes involved in (ADP-ribosyl)ation and the cellular pathways they function within. However, our understanding of how these enzymes are regulated is lacking and demands further investigation. In this proposal I seek to redress this.I have provided promising preliminary data identifying a novel uncharacterised interactor of PARP1 involved in the DDR. I expect that this novel protein will have a fundamental role in PARP1 biology in cells given that the two have co-evolved and form a protein complex in cells. I will implement newly available cutting-edge technologies, such as CRISPR-Cas9 and quantitative cell biology approaches, into an interdisciplinary strategy involving genetics, cell biology, structural biology and biochemistry. This strategy will allow me to address the following research objectives: (1) elucidate the function of this protein complex in genome maintenance (2) determine the atomic structure of the complex (3) define the physiological function of the protein complex using genetic mouse models.This timely and holistic approach will allow me to answer crucial outstanding questions related to the regulation of (ADP-ribosyl)ation signalling for the first time. Consequently, this will be the first mechanistic study of its function and therefore my research objectives are likely to yield original insights into novel aspects of (ADP-ribosyl)ation signalling.The objectives described in this proposal will enhance my potential to become an independent investigator by promoting the diversification of my technical competences through training at a world-leading institute and host laboratory. Therefore, the proposal is well aligned with the over-arching aims of the Work Programme.
Original text from CORDIS.
Participants
- THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD · OxfordCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union