Award details

Investigating the Role of DHX9 in the maintenance of genome stability

Reference	BB/P021387/1
Principal Investigator / Supervisor	Professor Kevin Hiom
Co-Investigators / Co-Supervisors
Institution	University of Dundee
Department	Cellular Medicine
Funding type	Research
Value (£)	448,621
Status	Completed
Type	Research Grant
Start date	01/11/2017
End date	30/06/2021
Duration	44 months

Abstract

Failure to maintain the structural and genetic integrity of chromosomes is linked with onset of a wide variety of diseases including neural-degeneration, immunodeficiency, premature ageing and cancer. While DNA damage can be caused through exposure to agents in our environment it also occurs naturally from endogenous sources such as reactive oxygen species produced through oxygen metabolism. Another source of genomic instability that is less well understood, occurs in dividing cells, through conflicts between DNA replication and transcription. Since these fundamental processes occur concurrently in dividing cells on there is the potential for potentially harmful 'collisions' between the replication and transcription machinery. Conflict are thought to be particularly prevalent in cells that are divide rapidly due to up-regulation of growth promoting genes. Failure to coordinate these processes can lead to the generation of harmful DNA/RNA structures such as R-loops and DNA breaks, leading to chromosomal abnormalities. We recently showed that SFPQ is an mRNA processing protein required for DNA replication and when defective causes profound replication stress, growth arrest and cell death n cells. More recently we identified a second RNA binding protein, DHX9, that restores growth in SFPQ defective cells when it is defective. In other words replication stress, growth arrest and cell death that characterize SFPQ-defective cells, are dependent on the activity of DHX9. We will investigate the function of DHX9 to understand its role in DNA replication and DNA repair and determine how it is linked to its role in transcription. Our hypothesis is that SFPQ and DHX9 play a role in coordinating DNA replication and transcription to avoid harmful genomic instability and promote healthy growth of cells and tissues.

Summary

The processes of duplicating our genetic material (DNA) to enable our cells to divide and the process of decoding and reading our genes to make the building blocks required for cell growth, are two crucial functions in dividing cells. Since, in cells, these processes occur concurrently, there is the potential for the molecular machines that perform these roles to collide or conflict, with potentially disastrous consequences, resulting in the generation of mutations and broken chromosomes that cause disease. We have identified two proteins that, we hypothesize, play an important role in coordinating the cells DNA synthesis machines and genetic code readers so that they avoid collision and catastrophe. In this project we will investigate how these processes are coordinated and what happens when this goes wrong. We hope that by studying this process we will be in a better position to understand how this fundamentally important process is carried out and identify genetic changes that cause it to go wrong, potentially leading to disease and/or aging.

Impact Summary

Successful completion of this project will have impact in several areas: Research/Academic: 1. How cells cells coordinate transcription and replication to facilitate gene expression, promote cell proliferation and maintain chromosome stability to prevent disease is central to human health. Our identification of DHX9 as a key regulator of gene expression, DNA replication and DNA repair has potential for significant impact on our understanding of the maintenance of genome stability and how cells respond to DNA damage caused by conflicts between DNA replication and transcription machinery. 2. The development of new reagents using genome editing will provide valuable resources for the further study of the DNA damage response. Clinical and patient: 1. The DHX9 in cell growth and proliferation and its influence on cellular response to therapeutic DNA damaging agents will impact on the stratification of patients for drug treatment. 2. Greater understanding of DHX9 will permit the identification of potentially pathological mutations in patients that might serve as diagnostic or prognostic markers in disease. Pharmaceutical: 1. As a regulator of cell growth and proliferation DHX9 might has potential as a target for cancer treatments. 2. Stratification of patients for clinical trials, based on the status of SFPQ and DHX9, has potential to reduce risk and increase precision of potential cancer treatments. Public: The publication of cutting edge research and its dissemination to a lay audience through public engagement and outreach activity has the potential to increase public support for basic research, engage the public in the promotion of well being and educate the public about science.

Committee	Research Committee C (Genes, development and STEM approaches to biology)
Research Topics	X – not assigned to a current Research Topic
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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