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Related Concept Videos

Viral Mutations00:36

Viral Mutations

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A mutation is a change in the sequence of bases of DNA or RNA in a genome. Some mutations occur during replication of the genome due to errors made by the polymerase enzymes that replicate DNA or RNA. Unlike DNA polymerase, RNA polymerase is prone to errors because it is not capable of “proofreading” its work. Viruses with RNA-based genomes, like HIV, therefore accrue mutations faster than viruses with DNA-based genomes. Because mutation and recombination provide the raw material...
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Translesion (TLS) polymerases rescue stalled DNA polymerases at sites of damaged bases by replacing the replicative polymerase and installing a nucleotide across the damaged site. Doing so, TLS allows additional time for the cell to repair the damage before resuming regular DNA replication.
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Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
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Retroviruses have a single-stranded RNA genome that undergoes a special form of replication. Once the retrovirus has entered the host cell, an enzyme called reverse transcriptase synthesizes double-stranded DNA from the retroviral RNA genome. This DNA copy of the genome is then integrated into the host’s genome inside the nucleus via an enzyme called integrase. Consequently, the retroviral genome is transcribed into RNA whenever the host’s genome is transcribed, allowing the...
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The basic reaction of homologous recombination (HR) involves two chromatids that contain DNA sequences sharing a significant stretch of identity. One of these sequences uses a strand from another as a template to synthesize DNA in an enzyme-catalyzed reaction. The final product is a novel amalgamation of the two substrates. To ensure an accurate recombination of sequences, HR is restricted to the S and G2 phases of the cell cycle. At these stages, the DNA has been replicated already and the...
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Related Experiment Video

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Determining 3'-Termini and Sequences of Nascent Single-Stranded Viral DNA Molecules during HIV-1 Reverse Transcription in Infected Cells
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Resolution of Specific Nucleotide Mismatches by Wild-Type and AZT-Resistant Reverse Transcriptases during HIV-1

Siarhei Kharytonchyk1, Steven R King1, Clement B Ndongmo1

  • 1Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI 48109-5620, USA.

Journal of Molecular Biology
|April 15, 2016
PubMed
Summary

Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) errors drive genetic variation. This study reveals distinct mechanisms of mismatch resolution by wild-type and AZT-resistant RT during HIV-1 replication.

Keywords:
forced copy-choice recombinationretroviral error mechanisms

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Determining 3'-Termini and Sequences of Nascent Single-Stranded Viral DNA Molecules during HIV-1 Reverse Transcription in Infected Cells
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Area of Science:

  • Virology
  • Molecular Biology
  • Genetics

Background:

  • HIV-1 genetic variation arises from errors made by reverse transcriptase (RT).
  • RT's lack of proofreading and limited nucleotide excision contribute to mutations and drug resistance.
  • Previous studies on mismatch resolution were limited to in vitro experiments.

Purpose of the Study:

  • To develop a novel system for studying mismatched base pair resolution during HIV-1 replication in cultured cells.
  • To compare the mismatch resolution mechanisms of wild-type (WT) RT and an AZT-resistant (AZT(R)) RT.
  • To elucidate the role of RT fidelity in HIV-1 mutagenesis.

Main Methods:

  • Development of a novel vector system to induce template switching and generate mismatched reverse transcription intermediates.
  • Comparison of proviral products from WT RT and AZT-resistant RT (carrying D67N, K70R, D215F, K219Q mutations).
  • Analysis of mismatch resolution outcomes, including nucleotide excision and primer strand misalignment.

Main Results:

  • Both WT and AZT(R) RT predominantly extended mismatches (>90% of proviruses).
  • AZT(R) RT did not show increased terminal nucleotide excision compared to WT RT.
  • Significant differences in resolving a specific dC-rC mispair were observed: WT RT excised or prematurely switched templates, while AZT(R) RT caused deletions via dislocation mutagenesis.

Conclusions:

  • HIV-1 RT exhibits a high capacity for mismatch extension during replication.
  • Wild-type and AZT-resistant RT possess distinct repertoires for resolving aberrant replication intermediates.
  • Nucleotide discrimination and mismatch extension interplay significantly in driving HIV-1 mutagenesis.