Identification of the most damaging nsSNPs in the human CFL1 gene and their functional and structural impacts on cofilin-1 protein

Halder, Sajal Kumar; Rafi, Md. Oliullah; Shahriar, Esha Binte; Albogami, Sarah; El-Shehawi, Ahmed M.; Daullah, S M Muktasid Ud; Himel, Mahbubul Kabir; Emran, Talha Bin

doi:10.1016/j.gene.2022.146206

Cited by 11 publications

(12 citation statements)

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“…It influences the target's structural and functional relationships along with protein–ligand interactions that are crucial for therapeutic research. 57 Throughout the MD simulation, five parameters have been analyzed to measure the robustness of the protein structures. These parameters are the root-mean-square deviation (RMSD) of enzyme and the root-mean-square fluctuation (RMSF), Rg analysis, the H-bond analysis, Solvent accessible surface area (SASA) analysis.…”

Section: Discussionmentioning

confidence: 99%

Oxa-376 and Oxa-530 variants of β-lactamase: computational study uncovers potential therapeutic targets ofAcinetobacter baumannii

et al. 2022

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Section: Discussionmentioning

confidence: 99%

Oxa-376 and Oxa-530 variants of β-lactamase: computational study uncovers potential therapeutic targets ofAcinetobacter baumannii

et al. 2022

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Section: Introductionmentioning

confidence: 96%

“…Global Cfl1 knockout mouse embryos have defective neural crest migration, diminished apical localisation of neuroepithelial actomyosin, fully penetrant failure of cranial neural tube closure causing exencephaly, and longer PNPs than somite stage-matched wildtype embryos suggesting predisposition to spina bifida (21, 34, 35). CFL1 genetic variants have also previously been associated with increased spina bifida risk in humans (36, 37). However, global developmental delay and the likely multiplicity of CFL1 functions in different tissues limit the use of global knockout embryos for mechanistic studies into its non-redundant functions in different cell types.…”

Section: Introductionmentioning

confidence: 99%

CFL1-dependent dynamicity of surface ectoderm filopodia-like protrusions enhances neurulation zippering speed in mice

Marshall,

Krstevski,

Croswell

et al. 2023

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Progression of caudally-directed embryonic neural tube closure must exceed that of body axis elongation, otherwise closure is incomplete and neural tube defects arise. Genetic deletion and pharmacological antagonism studies establish the critical role of actomyosin regulation in this closure process in mice, but many models of impaired F-actin regulation are limited by early embryonic lethality, which precludes mechanistic insightin vivo. Here, we test the physiological functions of the F-actin severing protein CFL1 by selective deletion in various tissues of mouse embryos undergoing neural tube closure. Loss of CFL1 in the cranial neuroepithelium diminishes selective apical localisation of F-actin and produces dysmorphic, asymmetrical headfolds which fail to meet at the dorsal midline, causing exencephaly, with partial penetrance. During spinal neurulation, neuroepithelial CFL1 is dispensable, but its expression in the surface ectoderm enhances the dynamicity of filopodia-like protrusions involved in the zippering process of midline epithelial fusion. Compared with littermate controls, spinal zippering speed is decreased by 30% in embryos lacking surface ectoderm CFL1 and approximately 30% of embryos develop spina bifida. These findings suggest that molecular-level cytoskeletal regulation by CFL1 sets the cellular-level dynamicity of filopodial extensions which limit tissue- level zippering speed necessary to fully close the neural tube.

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“…(1) The hypoxic tumor microenvironment creates an insufficient oxygen supply that fails to form stable oxidative adducts with damaged DNA, rendering tumors strongly resistant to radiation-induced killing by rapid DNA repair. , (2) Dysregulation of signaling pathways, especially gene upregulation, is the primary driving force for radiation resistance in GBM . Cofilin-1 (CFL1), a tumor progression marker deemed a “metastasis switch,” belongs to the actin-depolymerizing factor (ADF)/cofilin superfamily, − which is upregulated in RT-resistant tumors (i.e., rrGBM) . Further, tumor cell invasion into adjacent tissue is dependent on actin cytoskeleton remodeling, which forms invadopodia and produces forces to drive cell migration and infiltration. , Upregulated CFL1 induces F-actin cytoskeleton remodeling, accelerating tumor cell proliferation, migration, and clonal formation, thereby promoting radiation resistance.…”

Section: Introductionmentioning

confidence: 99%

Radiation-Triggered Selenium-Engineered Mesoporous Silica Nanocapsules for RNAi Therapy in Radiotherapy-Resistant Glioblastoma

et al. 2023

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Radiotherapy-resistant glioblastoma (rrGBM) remains a significant clinical challenge because of high infiltrative growth characterized by activation of antiapoptotic signal transduction. Herein, we describe an efficiently biodegradable selenium-engineered mesoporous silica nanocapsule, initiated by high-energy X-ray irradiation and employed for at-site RNA interference (RNAi) to inhibit rrGBM invasion and achieve maximum therapeutic benefit. Our radiation-triggered RNAi nanocapsule showed high physiological stability, good blood-brain barrier transcytosis, and potent rrGBM accumulation. An intratumoral RNAi nanocapsule permitted low-dose X-ray radiation-triggered dissociation for cofilin-1 knockdown, inhibiting rrGBM infiltration. More importantly, tumor suppression was further amplified by electron-affinity aminoimidazole products converted from metronidazole polymers under X-ray radiation-exacerbated hypoxia, which sensitized cell apoptosis to ionizing radiation by fixing reactive oxygen species-induced DNA lesions. In vivo experiments confirmed that our RNAi nanocapsule reduced tumor growth and invasion, prolonging survival in an orthotopic rrGBM model. Generally, we present a promising radiosensitizer that would effectively improve rrGBM-patient outcomes with low-dose X-ray irradiation.

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Identification of the most damaging nsSNPs in the human CFL1 gene and their functional and structural impacts on cofilin-1 protein

Cited by 11 publications

References 100 publications

Oxa-376 and Oxa-530 variants of β-lactamase: computational study uncovers potential therapeutic targets ofAcinetobacter baumannii

Oxa-376 and Oxa-530 variants of β-lactamase: computational study uncovers potential therapeutic targets ofAcinetobacter baumannii

CFL1-dependent dynamicity of surface ectoderm filopodia-like protrusions enhances neurulation zippering speed in mice

Radiation-Triggered Selenium-Engineered Mesoporous Silica Nanocapsules for RNAi Therapy in Radiotherapy-Resistant Glioblastoma

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