scholarly journals Integration of the DNA Damage Response with Innate Immune Pathways

10.5772/24735 ◽  
2011 ◽  
Author(s):  
Gordon M. ◽  
Stephan Gasser
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Innate Immune ◽  
Damage Response ◽  
Immune Pathways

scholarly journals Nucleic Acid Immunity and DNA Damage Response: New Friends and Old Foes

2021 ◽  
Vol 12 ◽  
Author(s):  
Clara Taffoni ◽  
Alizée Steer ◽  
Johanna Marines ◽  
Hanane Chamma ◽  
Isabelle K. Vila ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nucleic Acid ◽  
Nucleic Acids ◽  
Dna Damage Response ◽  
Immune Activation ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Fine Tuning ◽  
Innate Immune Activation ◽  
Damage Response

The maintenance of genomic stability in multicellular organisms relies on the DNA damage response (DDR). The DDR encompasses several interconnected pathways that cooperate to ensure the repair of genomic lesions. Besides their repair functions, several DDR proteins have emerged as involved in the onset of inflammatory responses. In particular, several actors of the DDR have been reported to elicit innate immune activation upon detection of cytosolic pathological nucleic acids. Conversely, pattern recognition receptors (PRRs), initially described as dedicated to the detection of cytosolic immune-stimulatory nucleic acids, have been found to regulate DDR. Thus, although initially described as operating in specific subcellular localizations, actors of the DDR and nucleic acid immune sensors may be involved in interconnected pathways, likely influencing the efficiency of one another. Within this mini review, we discuss evidences for the crosstalk between PRRs and actors of the DDR. For this purpose, we mainly focus on cyclic GMP-AMP (cGAMP) synthetase (cGAS) and Interferon Gamma Inducible Protein 16 (IFI16), as major PRRs involved in the detection of aberrant nucleic acid species, and components of the DNA-dependent protein kinase (DNA-PK) complex, involved in the repair of double strand breaks that were recently described to qualify as potential PRRs. Finally, we discuss how the crosstalk between DDR and nucleic acid-associated Interferon responses cooperate for the fine-tuning of innate immune activation, and therefore dictate pathological outcomes. Understanding the molecular determinants of such cooperation will be paramount to the design of future therapeutic approaches.

Abstract C105: DNA damage response deficiency (DDRD) in breast cancer is associated with a STING-dependent innate immune response

2015 ◽  
Author(s):  
Eileen E. Parkes ◽  
Steven M. Walker ◽  
Nuala McCabe ◽  
Laura E. Taggart ◽  
Laura Hill ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Damage Response

scholarly journals Regulation of the Cell-Intrinsic DNA Damage Response by the Innate Immune Machinery

2021 ◽  
Vol 22 (23) ◽  
pp. 12761
Author(s):  
Thomas J. Hayman ◽  
Peter M. Glazer
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Double Strand Breaks ◽  
Innate Immune ◽  
Genomic Integrity ◽  
Dna Double Strand Breaks ◽  
Strand Breaks ◽  
Immune Mediated ◽  
Damage Response

Maintenance of genomic integrity is crucial for cell survival. As such, elegant DNA damage response (DDR) systems have evolved to ensure proper repair of DNA double-strand breaks (DSBs) and other lesions that threaten genomic integrity. Towards this end, most therapeutic studies have focused on understanding of the canonical DNA DSB repair pathways to enhance the efficacy of DNA-damaging therapies. While these approaches have been fruitful, there has been relatively limited success to date and potential for significant normal tissue toxicity. With the advent of novel immunotherapies, there has been interest in understanding the interactions of radiation therapy with the innate and adaptive immune responses, with the ultimate goal of enhancing treatment efficacy. While a substantial body of work has demonstrated control of the immune-mediated (extrinsic) responses to DNA-damaging therapies by several innate immune pathways (e.g., cGAS–STING and RIG-I), emerging work demonstrates an underappreciated role of the innate immune machinery in directly regulating tumor cell-intrinsic/cell-autonomous responses to DNA damage.

scholarly journals Activating the DNA Damage Response and Suppressing Innate Immunity: Human Papillomaviruses Walk the Line

Pathogens ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 467 ◽  
Author(s):  
Claire D. James ◽  
Dipon Das ◽  
Molly L. Bristol ◽  
Iain M. Morgan
Keyword(s):  
Immune Response ◽  
Dna Damage ◽  
Life Cycle ◽  
Dna Damage Response ◽  
Innate Immune Response ◽  
Adaptive Immune Response ◽  
Viral Life Cycle ◽  
Human Papillomaviruses ◽  
Innate Immune ◽  
Damage Response

Activation of the DNA damage response (DDR) by external agents can result in DNA fragments entering the cytoplasm and activating innate immune signaling pathways, including the stimulator of interferon genes (STING) pathway. The consequences of this activation can result in alterations in the cell cycle including the induction of cellular senescence, as well as boost the adaptive immune response following interferon production. Human papillomaviruses (HPV) are the causative agents in a host of human cancers including cervical and oropharyngeal; HPV are responsible for around 5% of all cancers. During infection, HPV replication activates the DDR in order to promote the viral life cycle. A striking feature of HPV-infected cells is their ability to continue to proliferate in the presence of an active DDR. Simultaneously, HPV suppress the innate immune response using a number of different mechanisms. The activation of the DDR and suppression of the innate immune response are essential for the progression of the viral life cycle. Here, we describe the mechanisms HPV use to turn on the DDR, while simultaneously suppressing the innate immune response. Pushing HPV from this fine line and tipping the balance towards activation of the innate immune response would be therapeutically beneficial.

Abstract 4000: A DNA damage response deficiency (DDRD) group in breast cancer is associated with activation of the STING innate immune pathway and PD-L1 expression

2016 ◽  
Author(s):  
Eileen E. Parkes ◽  
Steven M. Walker ◽  
Nuala McCabe ◽  
Laura E. Taggart ◽  
Laura Hill ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Damage ◽  
Dna Damage Response ◽  
Innate Immune ◽  
Damage Response ◽  
Immune Pathway ◽  
Innate Immune Pathway

scholarly journals Answered and Unanswered Questions in Early-Stage Viral Vector Transduction Biology and Innate Primary Cell Toxicity for Ex-Vivo Gene Editing

2021 ◽  
Vol 12 ◽  
Author(s):  
Amanda Mary Dudek ◽  
Matthew Hebden Porteus
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Gene Editing ◽  
Ex Vivo ◽  
Early Stage ◽  
Innate Immune ◽  
Hematopoietic Stem ◽  
Damage Response ◽  
Vector Transduction

Adeno-associated virus is a highly efficient DNA delivery vehicle for genome editing strategies that employ CRISPR/Cas9 and a DNA donor for homology-directed repair. Many groups have used this strategy in development of therapies for blood and immune disorders such as sickle-cell anemia and severe-combined immunodeficiency. However, recent events have called into question the immunogenicity of AAV as a gene therapy vector and the safety profile dictated by the immune response to this vector. The target cells dictating this response and the molecular mechanisms dictating cellular response to AAV are poorly understood. Here, we will investigate the current known AAV capsid and genome interactions with cellular proteins during early stage vector transduction and how these interactions may influence innate cellular responses. We will discuss the current understanding of innate immune activation and DNA damage response to AAV, and the limitations of what is currently known. In particular, we will focus on pathway differences in cell line verses primary cells, with a focus on hematopoietic stem and progenitor cells (HSPCs) in the context of ex-vivo gene editing, and what we can learn from HSPC infection by other parvoviruses. Finally, we will discuss how innate immune and DNA damage response pathway activation in these highly sensitive stem cell populations may impact long-term engraftment and clinical outcomes as these gene-editing strategies move towards the clinic, with the aim to propose pathways relevant for improved hematopoietic stem cell survival and long-term engraftment after AAV-mediated genome editing.

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