cGAS in nucleus: The link between immune response and DNA damage repair

Abstract

As the first barrier of host defense, innate immunity sets up the parclose to keep out external microbial or virus attacks. Depending on the type of pathogens, several cytoplasm pattern recognition receptors exist to sense the attacks from either foreign or host origins, triggering the immune response to battle with the infections. Among them, cGAS-STING is the major pathway that mainly responds to microbial DNA, DNA virus infections, or self-DNA, which mainly comes from genome instability by-product or released DNA from the mitochondria. cGAS was initially found functional in the cytoplasm, although intriguing evidence indicates that cGAS exists in the nucleus where it is involved in the DNA damage repair process. Because the close connection between DNA damage response and immune response and cGAS recognizes DNA in length-dependent but DNA sequence–independent manners, it is urgent to clear the function balance of cGAS in the nucleus versus cytoplasm and how it is shielded from recognizing the host origin DNA. Here, we outline the current conception of immune response and the regulation mechanism of cGAS in the nucleus. Furthermore, we will shed light on the potential mechanisms that are restricted to be taken away from self-DNA recognition, especially how post-translational modification regulates cGAS functions.

DNA sensing in cancer: Pro-tumour and anti-tumour functions of cGAS–STING signalling

“…This may be a result of inherent CIN or further DNA damage from cancer therapy. Cancer cells can contribute to the anti-tumour responses generated against them through the secretion of IFN-Is and chemokines into the TME [ 9 , 11 , 63 , 77–79 ]. In that way, the STING signalling capacity of tumour cells themselves may shape their TME, with IFN-I signalling being associated with ‘hot’ tumours containing infiltrating DCs and T cells.…”

Cyclic GMP-AMP Synthase in Cancer Prevention

“…Firstly, the cGAS-STING pathway is designed to detect and respond to foreign or aberrant DNA in the cytosol, typically indicative of viral or bacterial infection. In the absence of infection, nuclear localization of cGAS helps prevent unwarranted immune responses and inflammation [ 42 ]. Secondly, cGAS functions as a DNA sensor, primarily detecting cytosolic DNA, which is abnormal in healthy cells.…”

How Does cGAS Avoid Sensing Self-DNA under Normal Physiological Conditions?

“…Cytosolic DNA could be degraded by TREX1, which could prevent inappropriate innate immune activation. 4 cGAS is located in the plasma membrane through interacting with PI(4,5)P2, which is least likely to detect self-DNA and prevent aberrant activation. The N-terminus of cGAS in humans has a phosphoinositidebinding domain and interacts selectively with phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) in the plasma membrane.…”

“…cGAS can be activated by dsDNA in a length-dependent but sequence-independent manner by binding the DNA phosphate backbone [4]. Thus, cGAS is activated not only by non-self DNA, such as DNA from DNA viruses or retroviruses, intracellular bacteria, and protozoa but also by self-DNA, including mitochondrial and nuclear DNA that gain access to the cytoplasm.…”