Intriguingly, MEFs, liver cells, lymphoid cells and skin cells isolated from mice exhibiting catalytically inactive RIPK1 die early and exert RIPK3 auto-phosphorylation, a hallmark of the necroptotic activation, whereas RIPK3 and MLKL deficient mice are protected from the cell death ex vivo and in vivo. ZBP1 can activate RIPK3 ( Upton et al., 2012), since it is capable to interact the RIPKs via its RHIM ( Fig. The protein z-DNA/RNA binding protein-1 ( ZBP1 also known as DAI) recognizes z-RNA or z-DNA structures, which are common as a consequence of a rapid viral RNA and DNA synthesis, but distinct from the B structure of the eukaryotic RNA or DNA. Gergely Imre, in International Review of Cell and Molecular Biology, 2020 3.2.2 Necroptosis via ZBP1 Z-DNA-forming sequences in the genome can generate large-scale deletions possibly due to DNA repair processes and therefore can pose a danger to genome integrity in proliferating cells such as cancer cells.
A link of ZBP1 to cancer was suggested by the finding that ZBP1 is highly upregulated in the peritoneal lining tissue of mice bearing ascitic tumors. SGs and PDs regulate RNA metabolism and usually occur in response to stress conditions like heat shock, oxidative stress, hyperosmolarity, viral infection and UV irradiation, indicating that ZBP1 may be involved in mRNA sorting and metabolism.
The Zα domain was shown to regulate the cytosolic distribution of ZBP1, since ZBP1 lacking the Zα domain accumulated in large cytoplasmic granules, which interact with stress granules (SGs) and processing bodies (PDs). ZBP1 contains two N-terminal Z-DNA binding domains Zα and Zβ, which are known to induce and stabilize uncommon left-handed Z-form DNA, and a putative C-terminal DNA binding domain. However, DNA fragments shorter than 100 bp induce little type I IFN suggesting a minimum length requirement for ZBP1 binding to DNA. ZBP1 senses dsDNA irrespective of the sequence. In addition, ZBP1 can interact with receptor interacting protein kinase 1 (RIP1) and RIP3 leading to nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. Upon transfection of cells with double-stranded (ds) DNA, ZBP1 mediates a type I interferon (IFN) response by forming a complex with TANK binding kinase 1 (TBK1) and IFN regulatory factor 3 (IRF3). ZBP1 (Z-DNA binding protein 1, also named DAI/DLM-1) was the first reported cytosolic DNA sensor that functions independently of TLRs. Gasser, in Biological DNA Sensor, 2014 ZBP1 (DAI/DLM-1)
BioGRID Open Repository of CRISPR Screens (ORCS).RefSeqs of Annotated Genomes: Mus musculus Annotation Release 109 details. Location: 84 → 147 z-alpha Adenosine deaminase z-alpha domain Location: 8 → 72 Zalpha Z-DNA-binding domain in adenosine deaminases cl02659 Status: VALIDATED Description Transcript Variant: This variant (1) represents the longer transcript and encodes the longer isoform (1). See identical proteins and their annotated locations for NP_067369.2 Location: 8 → 72 z-alpha Adenosine deaminase z-alpha domain The resulting isoform (2) has a shorter and distinct C-terminus, compared to isoform 1. Status: VALIDATED Description Transcript Variant: This variant (2) differs in the 3' UTR and has multiple differences in the 3' coding region, compared to variant 1. See identical proteins and their annotated locations for NP_001132991.1 This section to the one reported in Genomic regions, Identify version mismatches by comparing the version of the RefSeq in These reference sequences are curated independently of the genomeĪnnotation cycle, so their versions may not match the RefSeq versions in the current These reference sequences exist independently of genome builds. Database of Single Nucleotide Polymorphisms (dbSNP).Database of Genomic Structural Variation (dbVar).Online Mendelian Inheritance in Man (OMIM).Database of Genotypes and Phenotypes (dbGaP).Structure (Molecular Modeling Database).Conserved Domain Search Service (CD Search).BLAST (Basic Local Alignment Search Tool).
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