Sensing of dangerous DNA

Gasser, Stephan; Zhang, Wendy Y.L.; Tan, Nikki Y.; Tripathi, Shubhita; Suter, Manuel A.; Chew, Zhi Huan; Khatoo, Muznah; Ngeow, Joanne; Cheung, Florence Shin Gee

doi:10.1016/j.mad.2016.09.001

Cited by 34 publications

(25 citation statements)

References 176 publications

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“…Radiotherapy induced a large population of tumour cells susceptible to cytotoxic killing, and the early administration of anti-PD-L1 prevented the growth of immunosuppressive cells and increased recruitment and activation of T cells (Azad et al 2017). Activation of stimulator of IFN genes (STING) can induce anti-tumour effects via type I interferons in various cancers including PCs in animal models (Gasser et al 2016). Administration of STING agonists resulted in marked increase of CD8 + T cell infiltration and upregulation of PD-L1 (Fu et al 2015).…”

Section: Pancreatic Cancer Microenvironmentmentioning

confidence: 99%

The role of the tumour microenvironment in immunotherapy

Gasser

Lim

Cheung

2017

Endocrine-Related Cancer

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Recent success in immunomodulating strategies in lung cancer and melanoma has prompted much enthusiasm in their potential to treat other advanced solid malignancies. However, their applications have shown variable success and are even ineffective against some tumours. The efficiency of immunotherapies relies on an immunogenic tumour microenvironment. The current field of cancer immunology has focused on understanding the interaction of cancer and host immune cells to break the state of immune tolerance and explain how molecular patterns of cytokines and chemokines affect tumour progression. Here, we review our current knowledge of how inherent properties of tumours and their different tumour microenvironments affect therapeutic outcome. We also discuss insights into recent multimodal therapeutic approaches that target tumour immune evasion and suppression to restore anti-tumour immunity.

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Section: Pancreatic Cancer Microenvironmentmentioning

confidence: 99%

The role of the tumour microenvironment in immunotherapy

Gasser

Lim

Cheung

2017

Endocrine-Related Cancer

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“…Ultimately, this response will determine whether the cell would live, senesce, or die. Failure to recognize and repair DSBs may lead to tissue ageing and disease (Ciccia and Elledge, 2010;Filippo et al, 2008;Gasser et al, 2016;Ribezzo et al, 2016;Shiloh, 2014).…”

Section: Introductionmentioning

confidence: 99%

SIRT6 is a DNA Double-Strand Break Sensor

Onn

Portillo

Ilić

et al. 2019

Preprint

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DNA double strand breaks are the most deleterious type of DNA damage. In this work, we show that SIRT6 directly recognizes DNA damage through a tunnel-like structure, with high affinity for double strand breaks. It relocates to sites of damage independently of signalling and known sensors and activates downstream signalling cascades for double strand break repair by triggering ATM recruitment, H2AX phosphorylation and the recruitment of proteins of the Homologous Recombination and Non-Homologous End Joining pathways. Our findings indicate that SIRT6 plays a previously uncharacterized role as DNA damage sensor, which is critical for initiating the DNA damage response (DDR). Moreover, other Sirtuins share some DSB binding capacity and DDR activation. SIRT6 activates the DDR, before the repair pathway is chosen, and prevents genomic instability. Our findings place SIRT6 at the top of the DDR and pave the road to dissect the contributions of distinct double strand break sensors in downstream signalling.

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“…Cells have evolved elaborate mechanisms to defend the integrity of DNA. Detection of damaged DNA activates complex DNA repair systems and activates innate immune pathways that alert the immune system to the presence of potentially damaged or infected cells [4,5]. In addition, recent studies found that genomic or mitochondrial DNA can accumulate in the cytosol of cells [5].…”

Section: Introductionmentioning

confidence: 99%

“…Detection of damaged DNA activates complex DNA repair systems and activates innate immune pathways that alert the immune system to the presence of potentially damaged or infected cells [4,5]. In addition, recent studies found that genomic or mitochondrial DNA can accumulate in the cytosol of cells [5]. Similar to damaged DNA, mislocalized DNA triggers innate immune responses including the production of type-I interferons and other inflammatory cytokines [6].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of PicoGreen variants for use in microscopy and flow cytometry

Khatoo

Yang

Gee

et al. 2019

Preprint

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PicoGreen is a fluorescent probe that binds dsDNA and forms a highly luminescent complex when compared to the free dye in solution. This unique probe is widely used in DNA quantitation assays but has limited application in flow cytometry and microscopy. Here we have investigated various PicoGreen variants for the ability to stain low amounts of cytosolic DNA present in many tumor cells. Analysis of stained cells by flow cytometry and fluorescent microscopy showed that certain variants improved the ability to stain low levels of cytosolic DNA when compared to the commercially available PicoGreen molecule.

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Sensing of dangerous DNA

Cited by 34 publications

References 176 publications

The role of the tumour microenvironment in immunotherapy

The role of the tumour microenvironment in immunotherapy

SIRT6 is a DNA Double-Strand Break Sensor

Evaluation of PicoGreen variants for use in microscopy and flow cytometry

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