DPC repair failure (SPRTN) as an upstream trigger of cGAS–STING activation

#1

As a follow-up on a recent post on cGAS-STING-driven inflammaging, a recent Science paper provides a clear example of what can activate this pathway independently of mitochondrial DNA leakage.

Loss of the DPC protease SPRTN caused accumulation of DNA–protein crosslinks, mitotic defects, and cytosolic DNA release, which in turn activated cGAS–STING signaling. In the mouse model, much of the pathology was mediated through this chronic innate immune activation, and inhibition of the pathway alleviated progeroid features.

So this is less about suppressing downstream effects of DNA leakage and more about an upstream failure of maintaining the genome that feeds into the same inflammatory axis.

Short note here: Research Note: When DNA–Protein Crosslinks Overwhelm Repair

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#2

How was that accomplished?

#3

The abstract states that they used both genetic and pharmacological inhibition of the cGAS–STING pathway. It doesn’t specify the exact compound in the abstract, so that detail would be in the full text.

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#4

So not much the average Joe can do with this one yet.

#5

Unfortunately yes. I can’t say I have looked into ways to modulate cGAS-STING pathway or to reduce the DNA-protein crosslinks, but the post RapAdmin posted gives some ideas of interventions that might be candidates for inhibiting cGAS-STING activation (I can’t wouch for any of the candidates having significant effects, that would require deep research on them). Optimally you would inhibit the DNA-protein crosslinks which are upstream but that’s most likely more difficult to do.

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