Neurodegenerative disorders are a family of incurable conditions. Among them, Alzheimer’s disease and tauopathies are the most common. Pathological features of these two disorders are synaptic loss, neuronal cell death and increased DNA damage. A key pathological protein for the onset and progression of the conditions is the protein tau, a microtubule-binding protein highly expressed in neurons and encoded by the MAPT (microtubule-associated protein tau) gene. Tau is predominantly a cytosolic protein that interacts with numerous other proteins and molecules. Recent findings, however, have highlighted new and unexpected roles for tau in the nucleus of neuronal cells. This review summarizes the functions of tau in the metabolism of DNA, describing them in the context of the disorders.

G-quadruplexes or G4s are non-canonical secondary structures of nucleic acids characterized by guanines arranged in stacked tetraplex arrays. Decades of research into these peculiar assemblies of DNA and RNA, fueled by the development and optimization of a vast array of techniques and assays, has resulted in a large amount of information regarding their structure, stability, localization, and biological significance in native systems. A plethora of articles have reported the roles of G-quadruplexes in multiple pathways across several species, ranging from gene expression regulation to RNA biogenesis and trafficking, DNA replication, and genome maintenance. Crucially, a large amount of experimental evidence has highlighted the roles of G-quadruplexes in cancer biology and other pathologies, pointing at these structurally unique guanine assemblies as amenable drug targets. Given the rapid expansion of this field of research, this review aims at summarizing all the relevant aspects of G-quadruplex biology by combining and discussing results from seminal works as well as more recent and cutting-edge experimental evidence. Additionally, the most common methodologies used to study G4s are presented to aid the reader in critically interpreting and integrating experimental data.

Primary cilia are commonly found on most quiescent, terminally differentiated cells and play a major role in the regulation of the cell cycle, cell motility, sensing, and cell–cell communication. Alterations in ciliogenesis and cilia maintenance are causative of several human diseases, collectively known as ciliopathies. A key determinant of primary cilia is the histone deacetylase HDAC6, which regulates their length and resorption and whose distribution is regulated by the death inducer-obliterator 3 (Dido3). Here, we report that the atypical protein kinase Haspin is a key regulator of cilia dynamics. Cells defective in Haspin activity exhibit longer primary cilia and a strong delay in cilia resorption upon cell cycle reentry. We show that Haspin is active in quiescent cells, where it phosphorylates threonine 3 of histone H3, a known mitotic Haspin substrate. Forcing Dido3 detachment from the chromatin prevents Haspin inhibition from impacting cilia dynamics, suggesting that Haspin activity is required for the relocalization of Dido3–HDAC6 to the basal body. Exploiting the zebrafish model, we confirmed the physiological relevance of this mechanism. Our observations shed light on a novel player, Haspin, in the mechanisms that govern the determination of cilia length and the homeostasis of mature cilia.

Chronic infections with intracellular pathogens such as Mycobacterium abscessus ( Mab ) pose significant health challenges due to their capacity to persist within host cells and evade immune responses. This study investigates the cellular responses to chronic Mab infection in macrophages, particularly focusing on cellular senescence. Using an in vitro model of chronic infection in murine alveolar-like macrophages, we found that Mab induces a senescent phenotype characterised by decreased proliferation, altered morphology, DNA damage signalling activation, and upregulation of senescence markers such as p21 and SA-β-galactosidase. Intriguingly, senescent macrophages secreted pro-inflammatory cytokines, consistent with a senescence-associated secretory phenotype (SASP), which promoted secondary senescence in neighbouring uninfected cells. This paracrine transmission of senescence underscores a potentially deleterious effect of Mab -induced SASP on tissue microenvironments, fostering a pro-inflammatory niche that may contribute to pathogen persistence. These findings highlight Mab -induced senescence as a key factor in chronic infection pathology, suggesting that targeting senescent cells and SASP-related pathways could enhance treatment outcomes in chronic bacterial infections.

Intracellular pathogens are ideal candidates for modelling the pathophysiology of chronic infection, as they hide within host cells and avoid conventional immune clearance through a controlled reshaping of cellular fate. This study unveils how the emerging intracellular pathogen Mycobacterium abscessus (Mab) reprograms alveolar macrophages towards a senescent state -a complex multifaced phenotype marked by proliferative arrest, distinctive morphological shifts, activation of DNA damage signalling cascade, and secretion of senescence-associated secretory phenotype (SASP) factors. Mab-induced DNA damage emerged as the primary driver of senescence, while SASP secretion acts as a molecular broadcaster, propagating secondary senescence in neighbouring, uninfected cells through paracrine signalling. This cascading wave of amplified senescence underscores a detrimental effect on the tissue microenvironment, potentially turning it into a chronic inflammatory niche that facilitates Mab persistence and immune evasion. By leveraging on the evidence of chronic infection-induced senescence, we prototyped a therapeutic approach where senolytic drugs selectively eradicated senescent cells and significantly reduced bacterial burden, similarly to antibiotics. This work molecularly dissects a previously overlooked axis of chronic infection-triggered senescence, wherein pathogen-induced DNA damage serves as the initiating event for starting the senescence program in host immune cells. More importantly, the results presented here demonstrate that eliminating infected senescent cells constitutes an unprecedented and effective host-directed therapy that can enhance treatment outcomes while bypassing the limitations imposed by rising antimicrobial resistance.

Intracellular pathogens are ideal candidates for modelling the pathophysiology of chronic infection, as they hide within host cells and avoid immune clearance by reshaping cellular fate. This study unveils how the intracellular pathogen Mycobacterium abscessus (Mab) reprograms alveolar macrophages towards a senescent state -a multifaced phenotype marked by proliferative arrest, distinctive morphological shifts, activation of DNA damage signalling cascade, and secretion of senescence-associated secretory phenotype (SASP) factors. Mab-induced DNA damage emerged as the primary driver of senescence, while SASP secretion acts as a molecular broadcaster, propagating secondary senescence in neighbouring, uninfected cells through paracrine signalling. This cascading wave of amplified senescence undermines the tissue microenvironment, turning it into a chronic inflammatory niche that facilitates Mab persistence and immune evasion. By leveraging evidence of chronic infection-induced senescence, we prototyped a therapeutic approach where the senolytic drug Navitoclax selectively eradicated senescent cells and significantly reduced bacterial burden, similarly to antibiotics.