Editors' ChoiceCancer

The two faces of cGAS in cancer and immunity

See allHide authors and affiliations

Sci. Signal.  20 Nov 2018:
Vol. 11, Issue 557, eaaw0850
DOI: 10.1126/scisignal.aaw0850

Cytosolic DNA sensing by cGAS promotes immunity, but its nuclear localization can promote tumorigenesis.

Sensing and repairing DNA damage is critical to cellular health. For example, DNA damage repair signaling maintains DNA integrity and suppresses tumorigenesis. The cytosolic DNA sensor cGAS (cyclic GMP-AMP synthase) stimulates the immune response to microbial infection. However, Liu et al. found that the localization of cGAS must be tightly controlled; nuclear cGAS promoted tumor growth by impairing DNA repair. In cultured fibroblasts and lung cancer cells, treatment with DNA-damaging agents induced importin-mediated translocation of cGAS to the nucleus, where it suppressed DNA repair. This function of cGAS was independent of its DNA-binding and enzymatic activities and of an inflammatory response, which mediate its conventional DNA-sensing function in innate immunity. Instead, biochemical analyses indicated that cGAS colocalized with phosphorylated H2AX (a marker of DNA damage) and bound to poly(ADP-ribose) (PAR) at DNA lesions, where it impaired PAR-mediated recruitment of repair-associated protein complexes. Further analysis and an RNA interference screen determined that phosphorylation of cGAS by B-lymphoid tyrosine kinase (BLK) caused cGAS to be retained in the cytosol. Mutating cGAS to prevent its phosphorylation or knocking down BLK promoted the nuclear translocation of cGAS, impaired DNA repair, and enhanced cell proliferation; whereas expressing a phosphomimetic mutant sequestered cGAS in the cytosol, promoted DNA damage repair, and suppressed cell proliferation. Overexpression of cGAS promoted the growth of lung cancer cell allografts in mice but, notably, sensitized cultured cells to DNA-damaging agents. The expression of cGAS is often increased and that of BLK is often decreased in non–small cell lung cancers. These findings indicate a tumorigenic mechanism behind these associations and identify a potential therapeutic sensitivity in patients. Furthermore, these findings should be considered when exploring therapeutically targeting BLK in some tumors, such as leukemia, and it may be particularly interesting to examine this mechanism in the context of virus-associated tumorigenesis.

Highlighted Article

View Abstract

Navigate This Article