ZNF451 collaborates with RNF8 to regulate RNF168 localization and amplify ubiquitination signaling to promote DNA damage repair and regulate radiosensitivity
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HAT1/HDAC2 mediated ACSL4 acetylation confers radiosensitivity by inducing ferroptosis in nasopharyngeal carcinoma
Protein acetylation modification plays important roles in various aspects of tumor progression. Ferroptosis driven by lethal lipid peroxidation is closely related to tumor development. Targeting ferroptosis has become a promising strategy. However, the crosstalk between protein acetylation and ferroptosis remains unclear. In present study, we found that the acetylation of acyl-CoA synthase long-chain family member 4 (ACSL4) enhances its protein stability and a double-edged sword regulation in nasopharyngeal carcinoma (NPC). On the one hand, ACSL4 could promote the malignant progress of tumors; on the other hand, it enhanced radiosensitivity by endowing NPC cells with ferroptosis-sensitive properties in vitro and in vivo. Mechanistically, histone acetyltransferase 1 (HAT1) directly promotes the acetylation of ACSL4 at lysine 383, and deacetylase sirtuin 3 (SIRT3) mediates the deacetylation of ACSL4. Meanwhile, another deacetylase histone deacetylase 2 (HDAC2) enhances ACSL4 acetylation through inhibiting the transcription of SIRT3. Acetylation of ACSL4 inhibits F-box protein 10 (FBXO10)-mediated K48-linked ubiquitination, resulting in enhanced protein stability of ACSL4. This study reveals the novel regulatory mechanism of ferroptosis-related protein from the perspective of protein acetylation, and provides a novel method for the radiosensitivity of NPC.
Targeting Chk1 and Wee1 kinases enhances radiosensitivity of 2D and 3D head and neck cancer models to X-rays and low/high-LET protons
Ionising radiation causes the introduction of DNA damage, more specifically double strand breaks (DSBs) and complex DNA damage (CDD), that induces cancer cell death leading to the therapeutic effect. To combat this, cells activate arrest at the G2/M checkpoint to allow for effective DNA damage repair, coordinated by the Chk1 and Wee1 protein kinases. Therefore, Chk1 and Wee1 are considered promising therapeutic targets to enhance the effectiveness of radiotherapy in cancer cell killing. Here, we have analysed the response of head and neck squamous cell carcinoma (HNSCC) cell lines, spheroids and patient-derived organoids to X-rays and proton beam therapy (PBT) in the presence of either a Chk1 (MK-8776) or a Wee1 (MK-1775) inhibitor. We demonstrate that inhibitors of Chk1 or Wee1 can significantly enhance the radiosensitivity of both 2D and 3D models of HNSCC to X-rays and PBT (performed at both low and high ionisation densities), and that this effect is caused through abrogation of the G2/M checkpoint causing the persistence of DSBs. Our results therefore suggest that targeting Chk1 and Wee1 kinases in combination with X-rays and PBT could represent a promising therapeutic avenue to enhance the clinical efficacy of HNSCC treatment.
Iron homeostasis and ferroptosis in muscle diseases and disorders: mechanisms and therapeutic prospects
The muscular system plays a critical role in the human body by governing skeletal movement, cardiovascular function, and the activities of digestive organs. Additionally, muscle tissues serve an endocrine function by secreting myogenic cytokines, thereby regulating metabolism throughout the entire body. Maintaining muscle function requires iron homeostasis. Recent studies suggest that disruptions in iron metabolism and ferroptosis, a form of iron-dependent cell death, are essential contributors to the progression of a wide range of muscle diseases and disorders, including sarcopenia, cardiomyopathy, and amyotrophic lateral sclerosis. Thus, a comprehensive overview of the mechanisms regulating iron metabolism and ferroptosis in these conditions is crucial for identifying potential therapeutic targets and developing new strategies for disease treatment and/or prevention. This review aims to summarize recent advances in understanding the molecular mechanisms underlying ferroptosis in the context of muscle injury, as well as associated muscle diseases and disorders. Moreover, we discuss potential targets within the ferroptosis pathway and possible strategies for managing muscle disorders. Finally, we shed new light on current limitations and future prospects for therapeutic interventions targeting ferroptosis.
Type 2 immunity in allergic diseases
Significant advancements have been made in understanding the cellular and molecular mechanisms of type 2 immunity in allergic diseases such as asthma, allergic rhinitis, chronic rhinosinusitis, eosinophilic esophagitis (EoE), food and drug allergies, and atopic dermatitis (AD). Type 2 immunity has evolved to protect against parasitic diseases and toxins, plays a role in the expulsion of parasites and larvae from inner tissues to the lumen and outside the body, maintains microbe-rich skin and mucosal epithelial barriers and counterbalances the type 1 immune response and its destructive effects. During the development of a type 2 immune response, an innate immune response initiates starting from epithelial cells and innate lymphoid cells (ILCs), including dendritic cells and macrophages, and translates to adaptive T and B-cell immunity, particularly IgE antibody production. Eosinophils, mast cells and basophils have effects on effector functions. Cytokines from ILC2s and CD4+ helper type 2 (Th2) cells, CD8 + T cells, and NK-T cells, along with myeloid cells, including IL-4, IL-5, IL-9, and IL-13, initiate and sustain allergic inflammation via T cell cells, eosinophils, and ILC2s; promote IgE class switching; and open the epithelial barrier. Epithelial cell activation, alarmin release and barrier dysfunction are key in the development of not only allergic diseases but also many other systemic diseases. Recent biologics targeting the pathways and effector functions of IL4/IL13, IL-5, and IgE have shown promising results for almost all ages, although some patients with severe allergic diseases do not respond to these therapies, highlighting the unmet need for a more detailed and personalized approach.
RECQL4 requires PARP1 for recruitment to DNA damage, and PARG dePARylation facilitates its associated role in end joining
RecQ helicases, highly conserved proteins with pivotal roles in DNA replication, DNA repair and homologous recombination, are crucial for maintaining genomic integrity. Mutations in RECQL4 have been associated with various human diseases, including Rothmund–Thomson syndrome. RECQL4 is involved in regulating major DNA repair pathways, such as homologous recombination and nonhomologous end joining (NHEJ). RECQL4 has more prominent single-strand DNA annealing activity than helicase activity. Its ability to promote DNA damage repair and the precise role of its DNA annealing activity in DNA repair are unclear. Here we demonstrate that PARP1 interacts with RECQL4, increasing its single-stranded DNA strand annealing activity. PARP1 specifically promoted RECQL4 PARylation at both its N- and C-terminal regions, promoting RECQL4 recruitment to DNA double-strand breaks (DSBs). Inhibition or depletion of PARP1 significantly diminished RECQL4 recruitment and occupancy at specific DSB sites on chromosomes. After DNA damage, PARG dePARylated RECQL4 and stimulated its end-joining activity. RECQL4 actively displaced replication protein A from single-stranded DNA, promoting microhomology annealing in vitro. Furthermore, depletion of PARP1 or RECQL4 substantially impacted classical-NHEJ- and alternative-NHEJ-mediated DSB repair. Consequently, the combined activities of PARP1, PARG and RECQL4 modulate DNA repair.
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