Editors' ChoiceCell Biology

Leaky nuclei lead to senescence

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Sci. Signal.  12 Sep 2017:
Vol. 10, Issue 496, eaap9030
DOI: 10.1126/scisignal.aap9030

A pathway that senses microbial DNA also promotes senescence in cells with cytosolic chromatin fragments.

The detection of cytosolic doubled-stranded DNA, such as from invading microbes, stimulates the enzyme cGAS, resulting in the activation of the adaptor STING pathway and expression of interferon-stimulated genes. Glück et al. found that the cGAS-STING pathway also detected cytosolic chromatin fragments, which are present in senescent cells that have undergone cell cycle arrest and no longer proliferate. Both cGAS and STING triggered senescence in mouse embryonic fibroblasts (MEFs) or WI-38 cells in a paracrine manner, potentially through type I interferons. Breakdown of the nuclear envelope caused by knockdown of the nuclear envelope component lamin B1 resulted in increased interferon-stimulated gene expression. MEFs from cGAS- or STING-deficient mice or WI-38 human fibroblasts with knockdown of cGAS or STING were protected from senescence caused by various triggers, including serial passaging, oxidative stress, irradiation, and oncogene activation. Mice deficient in cGAS or STING showed reduced signs of senescence upon irradiation or oncogene activation. These results suggest that the cGAS-STING pathway promotes senescence, although this role may be context-specific (see Ruiz de Galarreta and Lujambio).

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