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Your search keyword '"Tumor Suppressor Protein"' showing total 2 results
Start Over Descriptor "Tumor Suppressor Protein" Journal molecular cell
2 results on '"Tumor Suppressor Protein"'

1. Visualization of direct and diffusion-assisted RAD51 nucleation by full-length human BRCA2 protein.

Author

Belan, Ondrej, Greenhough, Luke, Kuhlen, Lucas, Anand, Roopesh, Kaczmarczyk, Artur, Gruszka, Dominika T., Yardimci, Hasan, Zhang, Xiaodong, Rueda, David S., West, Stephen C., and Boulton, Simon J.

Subjects
*BRCA genes, *DOUBLE-strand DNA breaks, *SINGLE-stranded DNA, *NUCLEATION, *DNA repair
Abstract

Homologous recombination (HR) is essential for error-free repair of DNA double-strand breaks, perturbed replication forks (RFs), and post-replicative single-stranded DNA (ssDNA) gaps. To initiate HR, the recombination mediator and tumor suppressor protein BRCA2 facilitates nucleation of RAD51 on ssDNA prior to stimulation of RAD51 filament growth by RAD51 paralogs. Although ssDNA binding by BRCA2 has been implicated in RAD51 nucleation, the function of double-stranded DNA (dsDNA) binding by BRCA2 remains unclear. Here, we exploit single-molecule (SM) imaging to visualize BRCA2-mediated RAD51 nucleation in real time using purified proteins. We report that BRCA2 nucleates and stabilizes RAD51 on ssDNA either directly or through an unappreciated diffusion-assisted delivery mechanism involving binding to and sliding along dsDNA, which requires the cooperative action of multiple dsDNA-binding modules in BRCA2. Collectively, our work reveals two distinct mechanisms of BRCA2-dependent RAD51 loading onto ssDNA, which we propose are critical for its diverse functions in maintaining genome stability and cancer suppression. [Display omitted] • Single-molecule imaging of full-length human BRCA2 reveals RAD51 nucleation mechanism • BRCA2 can nucleate and stabilize RAD51 on ssDNA directly • BRCA2 can slide along dsDNA backbone and deliver RAD51 to ds-ssDNA junctions • BRCA2 DNA-binding modules differentially contribute to sliding and RAD51 nucleation Belan et al. exploit single-molecule imaging to reveal the mechanism of early steps of presynaptic RAD51 filament establishment by full-length human BRCA2 protein. BRCA2 nucleates and stabilizes RAD51 on ssDNA and ds-ssDNA junctions, either directly or through a diffusion-assisted delivery mechanism involving BRCA2 sliding on dsDNA. [ABSTRACT FROM AUTHOR]

Published
2023
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2. Complex Inhibitory Effects of Nitric Oxide on Autophagy

Author

Sara Imarisio, Sovan Sarkar, Andrea Williams, Guido Kroemer, Maurizio Renna, Angeleen Fleming, Cahir J. O'Kane, David C. Rubinsztein, Claudia Rose, Viktor I. Korolchuk, Shouqing Luo, Moisés García-Arencibia, Benjamin R. Underwood, Fleming, Angeleen [0000-0003-3721-7126], Underwood, Benjamin [0000-0003-3427-9487], O'Kane, Cahir [0000-0002-3488-2078], Rubinsztein, David [0000-0001-5002-5263], Apollo - University of Cambridge Repository, Sarkar, Sovan, Korolchuk, Viktor I., Renna, Maurizio, Imarisio, Sara, Fleming, Angeleen, Mazza, WILLIAM ANDREA, Garcia-Arencibia, Moise, Rose, Claudia, Luo, Shouqing, Underwood, Benjamin R., Kroemer, Guido, O'Kane, Cahir J., and Rubinsztein, David C.

Subjects
Autophagosome, mTORC1, HeLa Cell, chemistry.chemical_compound, Mice, 0302 clinical medicine, HEK293 Cell, Enzyme Inhibitor, Protein Isoforms, Enzyme Inhibitors, Phosphorylation, Membrane Protein, Class III Phosphatidylinositol 3-Kinase, Nuclear Protein, 0303 health sciences, Huntingtin Protein, Apoptosis Regulatory Protein, biology, TOR Serine-Threonine Kinase, TOR Serine-Threonine Kinases, Neurodegeneration, Nuclear Proteins, 3. Good health, Cell biology, I-kappa B Kinase, Nitric oxide synthase, Huntington Disease, NG-Nitroarginine Methyl Ester, Proto-Oncogene Proteins c-bcl-2, Beclin-1, Human, Nerve Tissue Proteins, Mechanistic Target of Rapamycin Complex 1, Nitric Oxide, Article, Nitric oxide, Cell Line, 03 medical and health sciences, Tuberous Sclerosis Complex 2 Protein, medicine, Autophagy, Animals, Humans, Mitogen-Activated Protein Kinase 8, Molecular Biology, 030304 developmental biology, Tumor Suppressor Protein, Animal, Protein, Tumor Suppressor Proteins, AMPK, Protein Isoform, Membrane Proteins, Proteins, Cell Biology, medicine.disease, Class III Phosphatidylinositol 3-Kinases, Rats, HEK293 Cells, chemistry, Multiprotein Complexes, Nerve Tissue Protein, biology.protein, Multiprotein Complexe, Rat, Nitric Oxide Synthase, Apoptosis Regulatory Proteins, 030217 neurology & neurosurgery, HeLa Cells
Abstract

Summary Autophagy, a major degradation process for long-lived and aggregate-prone proteins, affects various human processes, such as development, immunity, cancer, and neurodegeneration. Several autophagy regulators have been identified in recent years. Here we show that nitric oxide (NO), a potent cellular messenger, inhibits autophagosome synthesis via a number of mechanisms. NO impairs autophagy by inhibiting the activity of S-nitrosylation substrates, JNK1 and IKKβ. Inhibition of JNK1 by NO reduces Bcl-2 phosphorylation and increases the Bcl-2–Beclin 1 interaction, thereby disrupting hVps34/Beclin 1 complex formation. Additionally, NO inhibits IKKβ and reduces AMPK phosphorylation, leading to mTORC1 activation via TSC2. Overexpression of nNOS, iNOS, or eNOS impairs autophagosome formation primarily via the JNK1–Bcl-2 pathway. Conversely, NOS inhibition enhances the clearance of autophagic substrates and reduces neurodegeneration in models of Huntington's disease. Our data suggest that nitrosative stress-mediated protein aggregation in neurodegenerative diseases may be, in part, due to autophagy inhibition., Graphical Abstract Highlights ► NO inhibits autophagy by independently inhibiting JNK1 and IKKβ ► NO inhibits autophagic flux via mTOR and mTOR-independent routes ► NOS overexpression impairs autophagosome synthesis via JNK1–Bcl-2 pathway ► NOS inhibition induces autophagy and protects against neurodegeneration

Published
2011

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