Alerting the immune system to DNA damage: micronuclei as mediators

MacDonald, Kate; Benguerfi, Soraya; Harding, Shane M.

doi:10.1042/ebc20200016

Cited by 20 publications

(20 citation statements)

References 118 publications

(155 reference statements)

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“…DNA double-strand breaks are the most lethal lesions induced by ionizing radiation and can trigger a series of cellular DNA damage responses (DDRs). Recently, a review described the current evidence linking the DNA damage responses to activation of the immune response through micronuclei formation 35 . It has been demonstrated that proton therapy induced more DNA double-strand breaks and micronuclei than photon irradiation at equivalent doses (2–12 Gy) 36 .…”

Section: Discussionmentioning

confidence: 99%

Impact of proton therapy on antitumor immune response

Mirjolet

Nicol

Limagne

et al. 2021

Sci Rep

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Radiotherapy delivered using photons induces an immune response that leads to modulation of the tumor microenvironment. Clinical studies are ongoing to evaluate immune checkpoint inhibitors in association with photon radiotherapy. At present, there is no publication on the radio-induced immune response after proton therapy. Balb/c mice bearing subcutaneous CT26 colon tumors were irradiated by a single fraction of 16.4 Gy using a proton beam extracted from a TR24 cyclotron. RNA sequencing analysis was assessed at 3 days post-treatment. Proton therapy immune response was monitored by flow cytometry using several panels (lymphoid, myeloid cells, lymphoid cytokines) at 7 and 14 days post-irradiation. RNA-Seq functional profiling identified a large number of GO categories linked to “immune response” and “interferon signaling”. Immunomonitoring evaluation showed induced tumor infiltration by immune cells. This is the first study showing the effect of proton therapy on immune response. These interesting results provide a sound basis to assess the efficacy of a combination of proton therapy and immune checkpoint inhibitors.

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Section: Discussionmentioning

confidence: 99%

Impact of proton therapy on antitumor immune response

Mirjolet

Nicol

Limagne

et al. 2021

Sci Rep

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“…Exogenous GFP-BLM expression reduced the frequency of micronuclei in U2OS 8 E6 cells (Figure 3D). Micronuclei contain either whole (centric) or partial (acentric) chromosomes depending on how they form (54)(55)(56)(57). Unrepaired DSBs lead to smaller acentric micronuclei (58), whereas segregation errors result in larger centric micronuclei (59,60).…”

Section: E6 Increases Micronuclei Frequency In Part Through Blm Reduc...mentioning

confidence: 99%

Beta HPV8 E6 Induces Micronuclei Formation and Promotes Chromothripsis

Dacus

Stancic

Pollina

et al. 2022

Preprint

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Cutaneous beta genus human papillomaviruses (β-HPV) are suspected to promote the development of non-melanoma skin cancer (NMSC) by destabilizing the host genome. Multiple studies have established the genome destabilizing capacities of β-HPV proteins E6 and E7 as a co-factor with UV. However, the E6 protein from β-HPV8 (HPV8 E6) induces tumors in mice without UV exposure. Here, we examined a UV-independent mechanism of HPV8 E6-induced genome destabilization. We showed that HPV8 E6 reduced the abundance of anaphase bridge resolving helicase, Bloom syndrome protein (BLM). The diminished BLM was associated with increased segregation errors and micronuclei. These HPV8 E6-induced micronuclei had disordered micronuclear envelopes yet retained replication and transcription competence. HPV8 E6 decreased antiproliferative responses to micronuclei and time-lapse imaging revealed HPV8 E6 promoted cells with micronuclei to complete mitosis. Finally, whole genome sequencing revealed that HPV8 E6 induced chromothripsis in 9 chromosomes. These data provide insight into mechanisms by which HPV8 E6-induces genome instability independent of UV exposure.

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“…In general, unresolved DNA damage can act as a mediator linking the DDR and immune recognition, and this can involve the formation of micronuclei as an initiating event in a cascade promoting genomic instability and innate immune responses ( 78 , 79 ). Moreover, genome instability and imperfect cell cycle checkpoints in tumor cells enhance formation of micronuclei, making them more susceptible to targeting of the innate immune response ( 5 , 22 , 79 ).…”

Section: Ddr In Innate Immunitymentioning

confidence: 99%

Function and Molecular Mechanism of the DNA Damage Response in Immunity and Cancer Immunotherapy

Yin

Lees‐Miller

et al. 2021

Front. Immunol.

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The DNA damage response (DDR) is an organized network of multiple interwoven components evolved to repair damaged DNA and maintain genome fidelity. Conceptually the DDR includes damage sensors, transducer kinases, and effectors to maintain genomic stability and accurate transmission of genetic information. We have recently gained a substantially improved molecular and mechanistic understanding of how DDR components are interconnected to inflammatory and immune responses to stress. DDR shapes both innate and adaptive immune pathways: (i) in the context of innate immunity, DDR components mainly enhance cytosolic DNA sensing and its downstream STimulator of INterferon Genes (STING)-dependent signaling; (ii) in the context of adaptive immunity, the DDR is needed for the assembly and diversification of antigen receptor genes that is requisite for T and B lymphocyte development. Imbalances between DNA damage and repair impair tissue homeostasis and lead to replication and transcription stress, mutation accumulation, and even cell death. These impacts from DDR defects can then drive tumorigenesis, secretion of inflammatory cytokines, and aberrant immune responses. Yet, DDR deficiency or inhibition can also directly enhance innate immune responses. Furthermore, DDR defects plus the higher mutation load in tumor cells synergistically produce primarily tumor-specific neoantigens, which are powerfully targeted in cancer immunotherapy by employing immune checkpoint inhibitors to amplify immune responses. Thus, elucidating DDR-immune response interplay may provide critical connections for harnessing immunomodulatory effects plus targeted inhibition to improve efficacy of radiation and chemotherapies, of immune checkpoint blockade, and of combined therapeutic strategies.

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Alerting the immune system to DNA damage: micronuclei as mediators

Cited by 20 publications

References 118 publications

Impact of proton therapy on antitumor immune response

Impact of proton therapy on antitumor immune response

Beta HPV8 E6 Induces Micronuclei Formation and Promotes Chromothripsis

Function and Molecular Mechanism of the DNA Damage Response in Immunity and Cancer Immunotherapy

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