The dark side of DNA

About the project

About the Project Project Title: The dark side of DNA Project Outline We think of DNA as a stable information source compartmentalised to the nucleus and mitochondria. When DNA enters the cytosol, it is recognised as a pathogen-associated molecular pattern by immune mechanisms that trigger inflammatory responses. However, a spectrum of diseases arise from mutations that increase formation or limit degradation of cytosolic DNA, even in the absence of infection. So, endogenous DNA must enter cytosol under normal conditions, but where this DNA comes from, why it is made and how it enters the cytosol remains largely mysterious. We have found that proliferating cells produce copious DNA that is exported from the nucleus, indicating that excess DNA synthesis is a normal, unavoidable part of nuclear metabolism. Many diseases including progerias (accelerated ageing conditions) are caused by mutations in DNA repair genes, while cytosolic chromatin is a characteristic feature of cellular senescence, raising questions as to whether DNA escaping the nucleus is a common factor in ageing and disease. We hypothesise that DNA egress from the nucleus is a major driver of disease and ageing, and is accentuated by mutations affecting DNA repair. This PhD project will use bespoke DNA sequencing methods to quantify and profile populations of cytosolic DNA, investigate formation mechanisms, and reveal mechanistic links to ageing and disease. Project Aims Refine methods to sequence cytosolic and secreted DNA in proliferating and quiescent cells carrying selected pathogenic mutations (WRN, ATM, ERCC1, RNASEH2, plus others that may be found to be relevant), then use DDR drugs to probe the DNA processing pathways generating this DNA. Apply these sequencing methods to tissue from young and old mice, to ask where cytosolic DNA accumulates and how this affects measured hallmarks of ageing. Once established, these methods could be applied to other tissues and/or clinical samples if available. Determine how different pathways of nuclear DNA egress lead to different immunogenic species, asking what is exported, where it goes, how it is processed and which immune receptors can be activated. This project will involve a mixture of wet and dry lab techniques. The successful candidate will generate sequencing libraries and optimise methods, then perform their own bioinformatic analysis. When implementing novel sequencing pathways, it is critical that the bioinformatics is performed with a thorough understanding of the method. All necessary training will be provided but a keen interest in bioinformatics would be an advantage. The project will be carried out within the Epigenetics Programme at the Babraham Institute, offering an outstanding interdisciplinary environment with expertise spanning epigenetics, development, signalling and ageing. Principal Supervisor Dr Jon Housley Email address: jon.houseley@babraham.ac.uk Fully funded BioSCaPe iDLA Studentship URL link to personal profile page or website: Jon Houseley » Babraham Institute Further details about the BioSCaPe iDLA including how to apply can be found here The applications deadline for all PhD studentships: 8 th December 2027 Please note interviews will be held the week commencing 18 th January 2027 Students will not be able to take up an award unless they meet all University eligibility criteria and are successful in securing admission to the University. In addition, they will not be able to apply for a visa (if needed) until they hold an unconditional offer from the University. Incomplete applications will not be considered. Bioscience South Cambridge doctoral training Partnership (BioSCaPe) is a transformative PhD programme designed to create the bioscience leaders of tomorrow. Based in the heart of the world-leading Cambridgeshire bioscience cluster, BioSCaPe offers an unparalleled opportunity to combine cutting-edge research with entrepreneurial and leadership skills. BioSCaPe is a partnership between four world-leading research organisations; the Babraham Institute, Wellcome Sanger Institute, MRC Laboratory of Molecular Biology, and the University of Cambridge in collaboration with major industry partners including AstraZeneca, Illumina, Alloy Therapeutics, and others, alongside the Babraham Research Campus and its network of bioscience companies. Starting October 2027, 4-year Research Studentships will be available, leading to a University of Cambridge PhD degree, in the laboratories of Dr Jon Housley, Dr Teresa Rayon and Dr Arianne Richard at the Babraham Institute. Details of the Babraham Institute’s interactive scientific programmes can be found on www.babraham.ac.uk . As a student at the Institute, you will have access to all of the outstanding science facilities , each one providing specialist equipment and expertise to support key research techniques and technologies.

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