Cellular senescence, which is characterized by an irreversible cell-cycle arrest accompanied by a distinctive secretory phenotype, can be induced through various intracellular and extracellular factors. Senescent cells that express the cell cycle inhibitory protein p16 have been found to actively drive naturally occurring age-related tissue deterioration and contribute to several diseases associated with ageing, including atherosclerosis and osteoarthritis. Various markers of senescence have been observed in patients with neurodegenerative diseases; however, a role for senescent cells in the aetiology of these pathologies is unknown. Here we show a causal link between the accumulation of senescent cells and cognition-associated neuronal loss. We found that the MAPTPS19 mouse model of tau-dependent neurodegenerative disease accumulates p16-positive senescent astrocytes and microglia. Clearance of these cells as they arise using INK-ATTAC transgenic mice prevents gliosis, hyperphosphorylation of both soluble and insoluble tau leading to neurofibrillary tangle deposition, and degeneration of cortical and hippocampal neurons, thus preserving cognitive function. Pharmacological intervention with a first-generation senolytic modulates tau aggregation. Collectively, these results show that senescent cells have a role in the initiation and progression of tau-mediated disease, and suggest that targeting senescent cells may provide a therapeutic avenue for the treatment of these pathologies.

Cellular effects of ionizing radiation (IR) are of great variety and level, but they are mainly damaging since radiation can perturb all important components of the cell, from the membrane to the nucleus, due to alteration of different biological molecules ranging from lipids to proteins or DNA. Regarding DNA damage, which is the main focus of this review, as well as its repair, all current knowledge indicates that IR-induced DNA damage is always more complex than the corresponding endogenous damage resulting from endogenous oxidative stress. Specifically, it is expected that IR will create clusters of damage comprised of a diversity of DNA lesions like double strand breaks (DSBs), single strand breaks (SSBs) and base lesions within a short DNA region of up to 15–20 bp. Recent data from our groups and others support two main notions, that these damaged clusters are: (1) repair resistant, increasing genomic instability (GI) and malignant transformation and (2) can be considered as persistent “danger” signals promoting chronic inflammation and immune response, causing detrimental effects to the organism (like radiation toxicity). Last but not least, the paradigm shift for the role of radiation-induced systemic effects is also incorporated in this picture of IR-effects and consequences of complex DNA damage induction and its erroneous repair.

The receptor-interacting protein 1 (RIPK1)/RIPK3 kinases play important roles in necroptosis that is closely linked to inflammatory response. Although the activation of necroptosis is well characterized, how necroptosis is tuned down is largely unknown. Here, we found that Parkin (also known as PARK2 ), an E3 ubiquitin ligase implicated in Parkinson’s disease and a tumor suppressor, regulates necroptosis and inflammation by regulating necrosome formation. Parkin prevents the formation of the RIPK1-RIPK3 complex by promoting polyubiquitination of RIPK3. Parkin is phosphorylated and activated by the cellular energy sensor AMP-activated protein kinase (AMPK). Parkin-deficiency potentiates the RIPK1-RIPK3 interaction, RIPK3 phosphorylation, and necroptosis. Importantly, Parkin deficiency enhances inflammation and inflammation-associated tumorigenesis. These findings demonstrate that the AMPK-Parkin axis negatively regulates necroptosis via inhibiting the RIPK1-RIPK3 complex formation and this regulation may serve as an important mechanism to fine-tune necroptosis and inflammation.

Cells respond to cytotoxic DNA double strand breaks by recruiting DNA repair proteins to the damaged site. This recruitment is dependent on ubiquitylation of adjacent chromatin areas by E3 ubiquitin ligases such as RNF8 and RNF168. RNF8 and RNF168 are recruited sequentially to the double strand breaks. However, it is unclear what dictates the sequential order and recruits RNF168 to the DNA lesion. Here, we reveal that Lethal(3)malignant brain tumor-like protein 2 (L3MBTL2) is the missing link between RNF8 and RNF168. We found that L3MBTL2 is recruited by MDC1 and subsequently ubiquitylated by the E3 ligase RNF8. Ubiquitylated L3MBTL2, in turn, facilitates recruitment of RNF168 to the DNA lesion and promotes DNA double strand break repair. These results identify L3MBTL2 as a key target of RNF8 following DNA damage and demonstrates how the DNA damage response pathway is orchestrated by ubiquitin signaling.