Interplay of cGAS with chromatin

Wischnewski, Marilena; Ablasser, Andrea

doi:10.1016/j.tibs.2021.05.011

Cited by 20 publications

(15 citation statements)

References 80 publications

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“…cGAS-STING signaling presents an evolutionarily highly conserved mechanism of immunity (26,27). Upon recognition of cytoplasmic DNA, cGAS uses ATP and GTP as substrates to synthesize cyclin GMP-AMP (cGAMP), which act as a second messenger to activate STING (28,29).…”

Section: Cgas-mediated Signaling Pathwaysmentioning

confidence: 99%

A Variety of Nucleic Acid Species Are Sensed by cGAS, Implications for Its Diverse Functions

et al. 2022

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Cyclic GMP-AMP synthase (cGAS) recognizes double-stranded DNA (dsDNA) derived from invading pathogens and induces an interferon response via activation of the key downstream adaptor protein stimulator of interferon genes (STING). This is the most classic biological function of the cGAS-STING signaling pathway and is critical for preventing pathogenic microorganism invasion. In addition, cGAS can interact with various types of nucleic acids, including cDNA, DNA : RNA hybrids, and circular RNA, to contribute to a diverse set of biological functions. An increasing number of studies have revealed an important relationship between the cGAS-STING signaling pathway and autophagy, cellular senescence, antitumor immunity, inflammation, and autoimmune diseases. This review details the mechanism of action of cGAS as it interacts with different types of nucleic acids, its rich biological functions, and the potential for targeting this pathway to treat various diseases.

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Section: Cgas-mediated Signaling Pathwaysmentioning

confidence: 99%

A Variety of Nucleic Acid Species Are Sensed by cGAS, Implications for Its Diverse Functions

et al. 2022

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“…In addition, cGAS recognizes cytoplasm dsDNA, an early event in DDR activation in GC cells [27], follows the activation of DSB repair and recruits repair factors such as RAD51; cGAS deletion impairs the initiation of DDR and prevents the activation of downstream DNA repair factors such as RAD51, XRCC2, BRCA1, etc. the interplay of cGAS with chromatin may be the critical mechanism [36] and warrants further investigation. A proteomics study also suggested that cGAS is associated with DNA-PK, the other molecular sensor for DNA damage [37], which highlights the possible role of nuclear cGAS in modulation of chromatin architecture [29].…”

Section: Discussionmentioning

confidence: 99%

cGAS regulates the DNA damage response to maintain proliferative signaling in gastric cancer cells

Liu¹,

LIU²,

Ren³

et al. 2021

Oncology Research

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“…DNA damage caused by genotoxic stresses or DNA damage stimulus (e.g., cytotoxic chemotherapy and radiation) can create cytosolic chromosomal fragments that may be recognized by cGAS, a cytosolic DNA sensor. Cytosolic exposure of chromosomal DNA by micronuclei rupture, breakage of chromatin bridges, or disintegration of micronuclei-like cytosolic chromatin fragments activates cGAS ( 34 ). Once bound to cytosolic DNA, activated cGAS can form dimers and multimer assemblies that undergo liquid–liquid phase separation to form biomolecular condensates that amplify cGAS activation ( 35 ).…”

Section: Ddr In Innate Immunitymentioning

confidence: 99%

“…Interestingly, cGAS is also found in the nucleus. Nuclear cGAS is inactivated by its acidic patch binding to nucleosome core particles, which prevents DNA binding, thus preventing autoreactivity ( 34 ). Moreover, nuclear cGAS is recruited to DNA damage sites by γH2AX, which promotes its interaction with Poly (ADP-ribose) polymerase 1 (PARP1) and impedes formation of PARP1-Timeless complex to thereby suppress HR but not NHEJ ( 43 , 44 ).…”

Section: Ddr In Innate Immunitymentioning

confidence: 99%

Function and Molecular Mechanism of the DNA Damage Response in Immunity and Cancer Immunotherapy

Yin

Lees‐Miller

et al. 2021

Front. Immunol.

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The DNA damage response (DDR) is an organized network of multiple interwoven components evolved to repair damaged DNA and maintain genome fidelity. Conceptually the DDR includes damage sensors, transducer kinases, and effectors to maintain genomic stability and accurate transmission of genetic information. We have recently gained a substantially improved molecular and mechanistic understanding of how DDR components are interconnected to inflammatory and immune responses to stress. DDR shapes both innate and adaptive immune pathways: (i) in the context of innate immunity, DDR components mainly enhance cytosolic DNA sensing and its downstream STimulator of INterferon Genes (STING)-dependent signaling; (ii) in the context of adaptive immunity, the DDR is needed for the assembly and diversification of antigen receptor genes that is requisite for T and B lymphocyte development. Imbalances between DNA damage and repair impair tissue homeostasis and lead to replication and transcription stress, mutation accumulation, and even cell death. These impacts from DDR defects can then drive tumorigenesis, secretion of inflammatory cytokines, and aberrant immune responses. Yet, DDR deficiency or inhibition can also directly enhance innate immune responses. Furthermore, DDR defects plus the higher mutation load in tumor cells synergistically produce primarily tumor-specific neoantigens, which are powerfully targeted in cancer immunotherapy by employing immune checkpoint inhibitors to amplify immune responses. Thus, elucidating DDR-immune response interplay may provide critical connections for harnessing immunomodulatory effects plus targeted inhibition to improve efficacy of radiation and chemotherapies, of immune checkpoint blockade, and of combined therapeutic strategies.

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Interplay of cGAS with chromatin

Cited by 20 publications

References 80 publications

A Variety of Nucleic Acid Species Are Sensed by cGAS, Implications for Its Diverse Functions

A Variety of Nucleic Acid Species Are Sensed by cGAS, Implications for Its Diverse Functions

cGAS regulates the DNA damage response to maintain proliferative signaling in gastric cancer cells

Function and Molecular Mechanism of the DNA Damage Response in Immunity and Cancer Immunotherapy

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