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 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.

scholarly journals PARP1 inhibitors trigger innate immunity via PARP1 trapping-induced DNA damage response

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Chiho Kim ◽  
Xu-Dong Wang ◽  
Yonghao Yu
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Dna Damage Response ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Relative Contribution ◽  
Innate Immune Signaling ◽  
Damage Response ◽  
Oncological Diseases ◽  
Parp1 Inhibitors

It is being increasingly appreciated that the immunomodulatory functions of PARP1 inhibitors (PARPi) underlie their clinical activities in various BRCA-mutated tumors. PARPi possess both PARP1 inhibition and PARP1 trapping activities. The relative contribution of these two mechanisms toward PARPi-induced innate immune signaling, however, is poorly understood. We find that the presence of the PARP1 protein with uncompromised DNA-binding activities is required for PARPi-induced innate immune response. The activation of cGAS-STING signaling induced by various PARPi closely depends on their PARP1 trapping activities. Finally, we show that a small molecule PARP1 degrader blocks the enzymatic activity of PARP1 without eliciting PARP1 trapping or cGAS-STING activation. Our findings thus identify PARP1 trapping as a major contributor of the immunomodulatory functions of PARPi. Although PARPi-induced innate immunity is highly desirable in human malignancies, the ability of ‘non-trapping’ PARP1 degraders to avoid the activation of innate immune response could be useful in non-oncological diseases.

scholarly journals DNA Damage Response and Oxidative Stress in Systemic Autoimmunity

2019 ◽  
Vol 21 (1) ◽  
pp. 55 ◽  
Author(s):  
Vassilis L. Souliotis ◽  
Nikolaos I. Vlachogiannis ◽  
Maria Pappa ◽  
Alexandra Argyriou ◽  
Panagiotis A. Ntouros ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Immune Response ◽  
Dna Damage ◽  
Autoimmune Diseases ◽  
Dna Damage Response ◽  
Lupus Erythematosus ◽  
Mononuclear Cells ◽  
Tissue Injury ◽  
Systemic Autoimmune Diseases ◽  
Damage Response

The DNA damage response and repair (DDR/R) network, a sum of hierarchically structured signaling pathways that recognize and repair DNA damage, and the immune response to endogenous and/or exogenous threats, act synergistically to enhance cellular defense. On the other hand, a deregulated interplay between these systems underlines inflammatory diseases including malignancies and chronic systemic autoimmune diseases, such as systemic lupus erythematosus, systemic sclerosis, and rheumatoid arthritis. Patients with these diseases are characterized by aberrant immune response to self-antigens with widespread production of autoantibodies and multiple-tissue injury, as well as by the presence of increased oxidative stress. Recent data demonstrate accumulation of endogenous DNA damage in peripheral blood mononuclear cells from these patients, which is related to (a) augmented DNA damage formation, at least partly due to the induction of oxidative stress, and (b) epigenetically regulated functional abnormalities of fundamental DNA repair mechanisms. Because endogenous DNA damage accumulation has serious consequences for cellular health, including genomic instability and enhancement of an aberrant immune response, these results can be exploited for understanding pathogenesis and progression of systemic autoimmune diseases, as well as for the development of new treatments.

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