Abstract
p53 binding protein-1 (53BP1) participates in checkpoint signaling during the DNA damage response (DDR) and during mitosis. In this study we report that 53BP1 aggregates in nuclear foci within syncytia elicited by the human immunodeficiency virus (HIV)-1 envelope. 53BP1 aggregation occurs as a consequence of nuclear fusion (karyogamy (KG)). It colocalizes partially with the promyelomonocytic leukemia protein (PML), and the ataxia telangiectasia mutated kinase (ATM), the two components of the DDR that mediate apoptosis induced by the HIV-1 envelope. ATM-dependent phosphorylation of 53BP1 on serines 25 and 1778 (53BP1S25P and 53BP1S1778P) occurs at these DNA damage foci. 53BP1S25P was also detected in syncytia present in the lymph nodes or frontal brain sections from HIV-1-infected carriers, as well as in peripheral blood mononucleated cells from HIV-1-infected individuals, correlating with viral load. Knockdown of 53BP1 caused HIV-1 envelope-induced syncytia to enter abnormal mitoses, leading to their selective destruction through mitochondrion-dependent and caspase-dependent pathways. In conclusion, depletion of 53BP1 triggers the demise of HIV-1-elicited syncytia through mitotic catastrophe.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adult
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Apoptosis / genetics
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Apoptosis / physiology
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Ataxia Telangiectasia Mutated Proteins
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism
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DNA Damage / genetics
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DNA Damage / physiology
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Giant Cells / metabolism
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HIV-1 / metabolism*
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HeLa Cells
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Humans
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Immunohistochemistry
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism*
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Male
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Mitosis / genetics
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Mitosis / physiology
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Phosphorylation
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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RNA Interference
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Tumor Suppressor p53-Binding Protein 1
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env Gene Products, Human Immunodeficiency Virus / metabolism
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env Gene Products, Human Immunodeficiency Virus / physiology
Substances
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Cell Cycle Proteins
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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TP53BP1 protein, human
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Tumor Suppressor Proteins
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Tumor Suppressor p53-Binding Protein 1
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env Gene Products, Human Immunodeficiency Virus
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ATM protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases