HIV accessory proteins versus host restriction factors

Current Opinion in Virology, Journal Year: 2013, Volume and Issue: 3(6), P. 692 - 699

Published: Nov. 15, 2013

Language: Английский

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SAMHD1 Restricts Herpes Simplex Virus 1 in Macrophages by Limiting DNA Replication

Journal of Virology, Journal Year: 2013, Volume and Issue: 87(23), P. 12949 - 12956

Published: Sept. 26, 2013

Macrophages play important roles in host immune defense against virus infection. During infection by herpes simplex 1 (HSV-1), macrophages acquire enhanced antiviral potential. Restriction of HSV-1 replication and progeny production is to prevent viral spread, but the cellular mechanisms that inhibit DNA are unknown. SAMHD1 was recently identified as a retrovirus restriction factor highly expressed macrophages. The protein both undifferentiated monocytes differentiated macrophages, retroviral limited cells modulation phosphorylation. It proposed block reverse transcription RNA into depleting deoxynucleotide triphosphates (dNTPs). Viruses with genomes do not employ during infection, their also dependent on intracellular dNTP concentrations. Here, we demonstrate restricts genome macrophage cell lines. Depleting THP-1 replication, while ectopic overexpression U937 repressed replication. did impact gene expression from incoming genomes. involved triphosphohydrolase activity partially overcome addition exogenous deoxynucleosides. Unlike retroviruses, affected phosphorylation status. Our results suggest functions broadly viruses nondividing

Language: Английский

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SAMHD1 is a single-stranded nucleic acid binding protein with no active site-associated nuclease activity

Nucleic Acids Research, Journal Year: 2015, Volume and Issue: 43(13), P. 6486 - 6499

Published: June 22, 2015

The HIV-1 restriction factor SAMHD1 is a tetrameric enzyme activated by guanine nucleotides with dNTP triphosphate hydrolase activity (dNTPase). In addition to this established activity, there have been series of conflicting reports as whether the also possesses single-stranded DNA and/or RNA 3′-5′ exonuclease activity. was purified using three chromatography steps, over which DNase largely separated from dNTPase but RNase persisted. Surprisingly, we found that catalytic and nucleotide activator site mutants no retained activities. Thus, cannot be associated any known binding site. Monomeric bind preferentially RNA, while form required for action bound weakly. ssRNA binding, not ssDNA, induces higher-order oligomeric states are distinct binds dNTPs. We conclude trace activities detected in preparations arise persistent contaminants co-purify HD active An vivo model suggested where alternates between mutually exclusive functions hydrolysis depending on pool levels presence viral ssRNA.

Language: Английский

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Heterozygous colon cancer-associated mutations of SAMHD1 have functional significance

Proceedings of the National Academy of Sciences, Journal Year: 2016, Volume and Issue: 113(17), P. 4723 - 4728

Published: April 11, 2016

Significance The three major DNA replication fidelity determinants are nucleotide selectivity, proofreading, and mismatch repair. Defects in the two latter now firmly associated with cancer. Nucleotide selectivity is affected by changes absolute or relative concentrations of dNTPs. Here, we show that hemizygous SAMHD1 +/− mouse embryos have increased dNTP pools compared wild-type controls heterozygous mutations inactivate frequently found colon cancers. We infer such cancer cells and, therefore, higher mutation rates. These observations suggest concentrations, which affect first determinant fidelity,

Language: Английский

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Nucleases Acting at Stalled Forks: How to Reboot the Replication Program with a Few Shortcuts

Annual Review of Genetics, Journal Year: 2017, Volume and Issue: 51(1), P. 477 - 499

Published: Nov. 27, 2017

In a lifetime, human being synthesizes approximately 2×10 16 meters of DNA, distance that corresponds to 130,000 times the between Earth and Sun. This daunting task is executed by thousands replication forks, which progress along chromosomes frequently stall when they encounter DNA lesions, unusual structures, RNA polymerases, or tightly-bound protein complexes. To complete synthesis before onset mitosis, eukaryotic cells have evolved complex mechanisms process restart arrested forks through coordinated action multiple nucleases, topoisomerases, helicases. this review, we discuss recent advances in understanding role regulation nucleases acting at stalled with focus on nucleolytic degradation nascent commonly referred as fork resection. We also effects deregulated resection genomic instability unscheduled activation interferon response under stress conditions.

Language: Английский

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