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Inhibition of polyomavirus ori-dependent DNA replication by mSin3B
1Department of Biochemistry, University of Missouri-Columbia, Columbia, Missouri 65211, USA.
Abstract:
When tethered in cis to DNA, the transcriptional corepressor mSin3B inhibits polyomavirus (Py) ori-dependent DNA replication in vivo. Histone deacetylases (HDACs) appear not to be involved, since tethering class I and class II HDACs in cis does not inhibit replication and treating the cells with trichostatin A does not specifically relieve inhibition by mSin3B. However, the mSin3B L59P mutation that impairs mSin3B interaction with N-CoR/SMRT abrogates inhibition of replication, suggesting the involvement of N-CoR/SMRT. Py large T antigen interacts with mSin3B, suggesting an HDAC-independent mechanism by which mSin3B inhibits DNA replication.
Insights
The transcriptional corepressor mSin3B inhibits polyomavirus DNA replication through interaction with N-CoR/SMRT, independent of histone deacetylases (HDACs). This finding reveals a novel mechanism for replication control.
Area of Science:
- Molecular Biology
- Virology
- Epigenetics
Background:
- The transcriptional corepressor mSin3B plays a role in gene regulation.
- Polyomavirus (Py) DNA replication is a critical process for viral propagation.
- Histone deacetylases (HDACs) are known epigenetic regulators.
Purpose of the Study:
- To investigate the mechanism by which mSin3B inhibits Py ori-dependent DNA replication.
- To determine the role of HDACs and N-CoR/SMRT in mSin3B-mediated replication inhibition.
Main Methods:
- Tethering mSin3B and HDACs in cis to DNA in vivo.
- Treating cells with trichostatin A (a HDAC inhibitor).
- Analyzing the effect of an mSin3B L59P mutation on replication inhibition.
- Investigating the interaction between Py large T antigen and mSin3B.
Main Results:
- mSin3B tethered in cis inhibits Py ori-dependent DNA replication.
- HDACs are not involved in this inhibition; tethering them did not inhibit replication, and trichostatin A did not relieve inhibition.
- A specific mutation (L59P) in mSin3B abrogated replication inhibition, implicating N-CoR/SMRT.
- Polyomavirus large T antigen interacts with mSin3B.
Conclusions:
- mSin3B inhibits Py DNA replication via an HDAC-independent mechanism.
- The interaction of mSin3B with N-CoR/SMRT is crucial for this inhibitory effect.
- Polyomavirus large T antigen's interaction with mSin3B suggests a novel pathway for replication control.