Investigating the mechanisms of DNA damage-dependent cGAS activation
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Embargo End Date
2026-07-19
ICR Authors
Authors
Davies, L
Document Type
Thesis or Dissertation
Date
2026-01-19
Date Accepted
Abstract
cGAS is a major sensor of double-stranded DNA. Upon DNA binding, cGAS produces the second
messenger cGAMP, which in turn activates innate immune responses such as inflammatory gene
expression, cell death, and senescence. Under unperturbed conditions, cGAS is prevented from
self-sensing through its inhibition on chromatin. Despite this, cGAS can be activated by genotoxic
stress, but the mechanism and regulation of this process remain unknown. Although most cGAS
activation models involve cytoplasmic DNA, a substantial pool of nuclear cGAS exists. Here, we
hypothesise that cGAS inhibition is relieved upon genotoxic stress, potentially activating nuclear
cGAS and leading to subsequent immune responses.
This study aimed to establish assays to measure cGAS activation to define the mechanisms by
which cGAS activation occurs following genotoxic stress. Since studying cGAS activation in cells
can prove difficult due to feedback control and cellular heterogeneity, I have established cell-free
Xenopus egg extracts to study cGAS activation. This model can now be used to assess the effects
of DNA damage and defined DNA damage structures on cGAS activity. However, irradiation and
aphidicolin treatment did not appear to cause cGAS activation in extract. This potentially correlates
with findings from our group obtained in cells, which indicated that DNA damage does not
generate a strong cGAS stimulus, and only activates cGAS in a minor fraction of cells. To begin to
understand the nature of this heterogeneity, I have set up and performed a whole kinome siRNA
microscopy based-screen using a novel cell-based reporter for cGAS activation developed in our
group and have identified some potential regulators of cGAS activation following DNA damage.
Collectively, these results provide insight into the mechanisms underlying cGAS activation and its
regulation and may provide a basis for future co-treatment strategies to boost cGAS activation
during anti-cancer therapy.
Citation
2026
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Genome Stab & Immunity