Cytoplasmic DNA in cancer cells: Several pathways that potentially limit DNase2 and TREX1 activities

Anindya, Roy

doi:10.1016/j.bbamcr.2022.119278

Cited by 11 publications

(7 citation statements)

References 110 publications

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“…The TREX1 gene is located on chromosome 3 and encodes a 314-amino-acid protein with an exonuclease domain at the amino-terminal region and a transmembrane domain at the carboxy-terminal region. 45 The C-terminal transmembrane domain is responsible for anchoring TREX1 to the endoplasmic reticulum, while the exonuclease domain remains in the cytoplasm. 46 TREX1 mutants with no exonuclease activity result in accumulated DNAs in the cytoplasm that trigger overexpression of type I IFNs through the cGAS-STING T A B L E 1 AGS-related genes and functions of their expression products.…”

Section: Trex1mentioning

confidence: 99%

“…TREX1 is a major DNA‐specific 3′ – 5′ exonuclease in mammalian cells that degrades single‐and double‐stranded DNA (ssDNA and dsDNA) to protect the body from inappropriate autoimmune activation 44 (Table 1). The TREX1 gene is located on chromosome 3 and encodes a 314‐amino‐acid protein with an exonuclease domain at the amino‐terminal region and a transmembrane domain at the carboxy‐terminal region 45 . The C‐terminal transmembrane domain is responsible for anchoring TREX1 to the endoplasmic reticulum, while the exonuclease domain remains in the cytoplasm 46 .…”

Section: Pathogenic Genesmentioning

confidence: 99%

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Aicardi–Goutières syndrome: A monogenic type I interferonopathy

Liu

Shi

2023

Scand J Immunol

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Aicardi–Goutières syndrome (AGS) is a rare monogenic autoimmune disease that primarily affects the brains of children patients. Its main clinical features include encephalatrophy, basal ganglia calcification, leukoencephalopathy, lymphocytosis and increased interferon‐α (IFN‐α) levels in the patient's cerebrospinal fluid (CSF) and serum. AGS may be caused by mutations in any one of nine genes (TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1, LSM11 and RNU7‐1) that result in accumulation of self‐nucleic acids in the cytoplasm or aberrant sensing of self‐nucleic acids. This triggers overproduction of type I interferons (IFNs) and subsequently causes AGS, the prototype of type I interferonopathies. This review describes the discovery history of AGS with various genotypes and provides the latest knowledge of clinical manifestations and causative genes of AGS. The relationship between AGS and type I interferonopathy and potential therapeutic methods for AGS are also discussed in this review.

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Section: Trex1mentioning

confidence: 99%

Section: Pathogenic Genesmentioning

confidence: 99%

Aicardi–Goutières syndrome: A monogenic type I interferonopathy

Liu

Shi

2023

Scand J Immunol

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“…DNase I is localized in serum, where it degrades the chromatin released from dead cells and prevents autoimmune diseases [42]. DNase II is localized in the lysosomes and is largely responsible for the clearance of DNA from dead cells and expelled nuclei [43]. TREX1, a major mammalian 3 -5 DNA-exonuclease, floats in the cytosol and prevents endogenous DNA accumulation [44].…”

Section: Gs] [De]h[de]h H[de]h (Where H Indicates a Hydrophobic Amino...mentioning

confidence: 99%

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

Zheng,

Chen,

Meurens

et al. 2023

IJMS

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cGAS is a cytosolic DNA sensor that activates innate immune responses by producing the second messenger 2′3′-cGAMP, which activates the adaptor STING. cGAS senses dsDNA in a length-dependent but sequence-independent manner, meaning it cannot discriminate self-DNA from foreign DNA. In normal physiological conditions, cellular DNA is sequestered in the nucleus by a nuclear envelope and in mitochondria by a mitochondrial membrane. When self-DNA leaks into the cytosol during cellular stress or mitosis, the cGAS can be exposed to self-DNA and activated. Recently, many studies have investigated how cGAS keeps inactive and avoids being aberrantly activated by self-DNA. Thus, this narrative review aims to summarize the mechanisms by which cGAS avoids sensing self-DNA under normal physiological conditions.

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“…In general, DNA damage can cause nucleus DNA to accumulate in the cytoplasm, which can activate immune response by the cytosol DNA immune receptors ( 105 – 110 ). Tumors and cancer cells that have DNA damage repair defects have more cytoplasm DNA enrichment and formed small but large impact DNA-containing structure: micronuclei ( 111 , 112 ). Cytoplasmic micronuclei, a small DNA-containing structure in cytosol, resulting from defective DNA replication, DNA damage repair, or mitosis error, is a biomarker of DNA damage and genome instability and is considered as the major elicitor to trigger the cGAS-STING–dependent autoimmune response.…”

Section: Dna Damage Repair and Immune Responsementioning

confidence: 99%

“…Therefore, controlling the availability of host DNA is essential to prevent aberrant pathway activation and inhibit autoimmune disease. There are several elegant mechanisms that exist to timely remove the abnormal DNA, such as DNaseII, TREX, and several DNA binding factors ( 111 , 120 ).…”

Section: Cross-talk Between Cgas-mediated Immune Response and Dna Dam...mentioning

confidence: 99%

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

et al. 2022

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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.

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Cytoplasmic DNA in cancer cells: Several pathways that potentially limit DNase2 and TREX1 activities

Cited by 11 publications

References 110 publications

Aicardi–Goutières syndrome: A monogenic type I interferonopathy

Aicardi–Goutières syndrome: A monogenic type I interferonopathy

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

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

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