Nuclear AIM2‐Like Receptors Drive Genotoxic Tissue Injury by Inhibiting DNA Repair

Abstract

Radiation is an essential preparative procedure for bone marrow (BM) transplantation and cancer treatment. The therapeutic efficacy of radiation and associated toxicity varies from patient to patient, making it difficult to prescribe an optimal patient-specific irradiation dose. The molecular determinants of radiation response remain unclear. AIM2-like receptors (ALRs) are key players in innate immunity and determine the course of infections, inflammatory diseases, senescence, and cancer. Here it is reported that mice lacking ALRs are resistant to irradiation-induced BM injury. It is shown that nuclear ALRs are inhibitors of DNA repair, thereby accelerate genome destabilization, micronuclei generation, and cell death, and that this novel function is uncoupled from their role in innate immunity. Mechanistically, ALRs bind to and interfere with chromatin decompaction vital for DNA repair. The finding uncovers ALRs as targets for new interventions against genotoxic tissue injury and as possible biomarkers for predicting the outcome of radio/chemotherapy.

“Other Than NLRP3” Inflammasomes: Multiple Roles in Brain Disease

“…Two successive oligonucleotide/oligosaccharide folds of the HIN-200 domain bind long double-strand DNA (dsDNA) fragments deriving from damaged nuclear and/or mitochondrial DNA or from infecting bacterial or viral pathogens (Veeranki and Choubey 2012). The HIN-200 domain also binds intranuclear DNA damaged sites (Hu B and others 2016; Jiang and others 2021).…”

“…ALR -knockout mice resisted such irradiation injuries, revealing that the AIM2 inflammasome assembles inside DNA-damaged nuclei and binds DNA harm sites, thereby inhibiting the DNA unpacking, which is crucially needed for DNA repair to occur. Consequently, ALR s advance genome instability, micronucleus formation, and cell death in ways disconnected from their innate immunity roles (Jiang and others 2021). Whether this mechanism operates within irradiated human brain cell nuclei remains to be ascertained.…”

Nucleic Acid Sensing Pathways in DNA Repair Targeted Cancer Therapy

“…Recent studies reveal that ALRs perform different functions outside the immune system. It has been demonstrated that DNA breaks are repaired more efficiently in mice and cells lacking ALRs (ALR −/− mice lack the entire ALR locus containing all 13 ALR genes on Chromosome 13), resulting in the stronger resistance to the genotoxic effects of irradiation and chemotherapy ( Brunette et al, 2012 ; Gray et al, 2016 ; Jiang et al, 2021 ). Mechanistically, nuclear ALRs limit DNA repair machinery access to damaged sites by binding the chromatin, and self-oligomerization promoted chromatin compaction.…”

KiiM retreat 2021: Local immunology to fit global need?

“…Toby Lawrence, King's College London and CIML, Marseilles, presented work exploring tumour heterogeneity directing his studies to myeloid cells and their diverse and divergent roles in defining tumour survival or suppression 3 . Moreover, Nelson Gekara, Wenner‐Gren Institute, Stockholm University, elucidated the role of the innate immune system in sensing DNA repair activity, as a central regulatory mechanism of health maintenance 4,5 . Immunologists, neurologists and psychologists are becoming increasingly aware of the importance of crosstalk between the immune system and the nervous system.…”

“…3 Moreover, Nelson Gekara, Wenner-Gren Institute, Stockholm University, elucidated the role of the innate immune system in sensing DNA repair activity, as a central regulatory mechanism of health maintenance. 4,5 Immunologists, neurologists and psychologists are becoming increasingly aware of the importance of crosstalk between the immune system and the nervous system. David Engblom, Center for Social and Affective Neuroscience, Linköping University, presented his fascinating work, including unpublished findings, exploring immune signalling triggered by psychological distress.…”