Z-DNA and Z-RNA in human disease

Herbert, Alan

doi:10.1038/s42003-018-0237-x

Cited by 182 publications

(151 citation statements)

References 100 publications

Supporting

Mentioning

148

Contrasting

Order By: Relevance

“…In keratinocytes, RIPK1 ablation or disruptive mutation of the RHIM of RIPK1 induces spontaneous ZBP1dependent necroptosis and triggers skin inflammation, indicating that RIPK1 acts as a molecular scaffold to inhibit ZBP1-RIPK3-MLKL signaling in a RHIM-dependent way (Dannappel et al, 2014;Lin et al, 2016;. ZBP1 contains two tandem N-terminal Z-form nucleic acid binding (Zα)-domains, which specifically interact with doublestranded (ds) nucleic acid helices in the Z-conformation, including Z-RNA and Z-DNA (Herbert, 2019). Others and our group have shown that engagement of ZBP1 upon virus infection crucially depended on nucleic acid sensing by intact Zα-domains (Maelfait et al, 2017;Sridharan et al, 2017;Thapa et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation

Devos

Tanghe

Gilbert

et al. 2020

Journal of Experimental Medicine

View full text Add to dashboard Cite

Aberrant detection of endogenous nucleic acids by the immune system can cause inflammatory disease. The scaffold function of the signaling kinase RIPK1 limits spontaneous activation of the nucleic acid sensor ZBP1. Consequently, loss of RIPK1 in keratinocytes induces ZBP1-dependent necroptosis and skin inflammation. Whether nucleic acid sensing is required to activate ZBP1 in RIPK1-deficient conditions and which immune pathways are associated with skin disease remained open questions. Using knock-in mice with disrupted ZBP1 nucleic acid–binding activity, we report that sensing of endogenous nucleic acids by ZBP1 is critical in driving skin pathology characterized by antiviral and IL-17 immune responses. Inducing ZBP1 expression by interferons triggers necroptosis in RIPK1-deficient keratinocytes, and epidermis-specific deletion of MLKL prevents disease, demonstrating that cell-intrinsic events cause inflammation. These findings indicate that dysregulated sensing of endogenous nucleic acid by ZBP1 can drive inflammation and may contribute to the pathogenesis of IL-17–driven inflammatory skin conditions such as psoriasis.

show abstract

Section: Introductionmentioning

confidence: 99%

Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation

Devos

Tanghe

Gilbert

et al. 2020

Journal of Experimental Medicine

View full text Add to dashboard Cite

show abstract

“…The idea that ADAR1 could interact with DNA structure dates back to original observations made by Rich and colleagues who suggested that the Z-alpha domain of ADAR1 recognizes an alternative left-handed DNA structure 12,13,34 . Over the years, a very strong case has been made for the existence of Z-DNA and its role in many biological processes, particularly transcriptional regulation [37][38][39][40] . Specifically, it has been reported that Z-DNA is related to both transcriptional activation 41,42 and inhibition 43,44 .…”

Section: Discussionmentioning

confidence: 99%

Dynamic DNA structure states interact with the RNA editing enzyme ADAR1 to modulate fear extinction memory

Zhao

et al. 2019

Preprint

View full text Add to dashboard Cite

RNA modification has recently emerged as an important mechanism underlying gene diversity linked to behavioral regulation. The conversion of adenosine to inosine by the ADAR family of enzymes is a particularly important RNA modification as it impacts the physiological readout of protein-coding genes. However, not all variants of ADAR appear to act solely on RNA. ADAR1 binds directly to DNA when it is in a non-canonical, left handed, "Z" conformation, but little is known about the functional relevance of this interaction. Here we report that ADAR1 binds to Z-DNA in an activity-dependent manner and that fear extinction learning leads to increased ADAR1 occupancy at DNA repetitive elements, with targets adopting a Z-DNA structure at sites of ADAR1 recruitment.Knockdown of ADAR1 leads to an inability to modify a previously acquired memory trace and this is associated with a concomitant change in DNA structure and a decrease in RNA editing. These findings suggest a novel mechanism of learning-induced gene regulation whereby ADAR1 physically interacts with Z-DNA in order to mediate its effect on RNA, and both are required for memory flexibility following fear extinction learning.

show abstract

“…Whether RNA or DNA serve as agonists for ZBP1 in RIPK1-deficient keratinocytes remains to be determined. Zα-domains found in ZBP1 and the RNA editing enzyme ADAR1 specifically bind to nucleic acids in the Z-conformation, including Z-RNA and Z-DNA (Herbert, 2019). How dsRNA or dsDNA are stabilised in the thermodynamically unfavourable Z-conformation in living cells is unknown.…”

Section: Zbp1 Activation By Endogenous Nucleic Acids Induces Necroptomentioning

confidence: 99%

“…In keratinocytes, ablation of RIPK1 or disruptive mutation of the RHIM of RIPK1 induces spontaneous ZBP1-dependent necroptosis and triggers skin inflammation, indicating that RIPK1 acts as a molecular scaffold to inhibit ZBP1-RIPK3-MLKL signalling in a RHIM-dependent way (Dannappel et al, 2014;Lin et al, 2016;. ZBP1 contains two tandem N-terminal Z-form nucleic acid binding (Zα)-domains, which specifically interact with double stranded (ds) nucleic acid helices in the Z-conformation, including Z-RNA and Z-DNA (Herbert, 2019). Others and our group have shown that engagement of ZBP1 upon virus infection crucially depended on nucleic acid sensing by intact Zα-domains (Maelfait et al, 2017;Sridharan et al, 2017;Thapa et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation

Devos

Tanghe

Gilbert

et al. 2020

Preprint

View full text Add to dashboard Cite

Aberrant detection of endogenous nucleic acids by the immune system can cause inflammatory disease. The scaffold function of the signalling kinase RIPK1 limits spontaneous activation of the nucleic acid sensor ZBP1. Consequently, loss of RIPK1 in keratinocytes induces ZBP1-dependent necroptosis and skin inflammation. Whether nucleic acid sensing is required to activate ZBP1 in RIPK1 deficient conditions and which immune pathways are associated with skin disease remained open questions. Using knock-in mice with disrupted ZBP1 nucleic acid binding activity, we report that sensing of endogenous nucleic acids by ZBP1 is critical in driving skin pathology characterised by antiviral and IL-17 immune responses. Inducing ZBP1 expression by interferons triggers necroptosis in RIPK1-deficient keratinocytes and epidermis-specific deletion of MLKL prevents disease, demonstrating that cell-intrinsic events cause inflammation. These findings indicate that dysregulated sensing of endogenous nucleic acid by ZBP1 can drive inflammation and may contribute to the pathogenesis of IL-17-driven inflammatory skin conditions such as psoriasis.SummaryDevos, Tanghe et al. find that the recognition of endogenous nucleic acids by the nucleic acid sensor ZBP1 causes necroptosis of RIPK1-deficient keratinocytes. This process drives the development of an inflammatory skin disease characterised by an IL-17 immune response.

show abstract

Z-DNA and Z-RNA in human disease

Cited by 182 publications

References 100 publications

Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation

Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation

Dynamic DNA structure states interact with the RNA editing enzyme ADAR1 to modulate fear extinction memory

Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation

Contact Info

Product

Resources

About