The cyclic GMP–AMP synthase (cGAS) is a central sensor of misplaced DNA that activates innate immune responses through STING signalling (1). While essential for antiviral defence and genome integrity surveillance, cGAS activity must be tightly regulated to prevent chronic inflammation (2). Recent findings show that cGAS activity is potently inhibited by nucleosome binding (3), but the precise mechanisms and regulatory checkpoints remain incompletely understood. This project will investigate how chromatin and nucleosomes control cGAS activation, using purified proteins and defined chromatin templates.
The student will reconstitute cGAS–DNA–chromatin interactions in vitro using single-molecule biophysics (C-Trap optical tweezers with integrated fluorescence microscopy). These assays will provide biophysical insights into how nucleosomes restrict or modulate cGAS activation on chromatin substrates (4). In parallel, the project will develop high-throughput biochemical assays to screen for small molecules that disrupt the inhibitory cGAS–nucleosome interaction. Candidate compounds will be validated biophysically and then tested in cellular models.
To establish physiological relevance, the student will integrate these findings into cellular models. The focus will be on understanding the extent to which chromatin-mediated inhibition of cGAS shapes cell fate. In senescent cells, persistent chromatin remodelling and nuclear envelope instability promote cGAS activation, but nucleosomes may act as an intrinsic brake on this response. In parallel, the student will examine cancer cell models in response to chemotherapy treatment. The student will assess the distribution of cGAS, activation of the cGAS/STING pathway, and their functional consequences, and how that is affected by cell cycle status and response to treatment.Using genetic and pharmacological perturbations, the project will test whether chromatin-based inhibition of cGAS can be modulated in these contrasting cellular states, thereby clarifying its role in inflammation, senescence, and tumorigenesis.
A further aim will be to investigate how genomic instability influences the chromatin-based regulation of cGAS. The SMC5/6 complex, a critical genome maintenance factor, safeguards against DNA damage and chromosome mis-segregation. We will use SMC5/6 depletion as a defined perturbation to induce genomic instability and and genome-wide profiling approaches test how this impacts cGAS activity. Together, these experiments will clarify how genome maintenance pathways intersect with chromatin-based inhibition to shape innate immune responses.
To apply for this studentship please visit our website and complete an application form by the deadline - https://lms.mrc.ac.uk/work-and-study/studentships/lms-4-year-phd-studentships/