From: Kofi on
While we would like to be able to minutely regulate methylation and
histone acetylation to deal with chronic diseases and aging, it may be
the case that we suffer damage from chronic diseases and aging precisely
because the body has to engage in a series of trade-offs to keep certain
viruses suppressed. Here is another example of epigenetics and viral
cycles, an add on to earlier work showing how butyrate can reawaken
dormant herpesviruses.

<http://www.sciencedaily.com/releases/2010/01/100114081547.htm>

Key Mechanism for the Proliferation of Epstein-Barr Virus Discovered

ScienceDaily (Jan. 15, 2010) � Scientists of Helmholtz Zentrum M�nchen
have elucidated a crucial mechanism in the lytic cycle of Epstein-Barr
virus. A team of researchers led by Professor Wolfgang Hammerschmidt
identified the function of a protein which plays a critical role in the
proliferation of the virus. The Epstein-Barr virus can induce cancer.

The findings, published in the current issue of Proceedings of the
National Academy of Sciences, represent a major step forward in
understanding tumor development.

The Epstein-Barr virus (EBV), a virus of the herpes family, has two
distinct life phases: After infecting a cell it first goes into a
resting phase. Under certain circumstances the virus can become active
-- and then induces tumor growth or promotes its synthesis in the cell.
Especially in patients with weakened immune systems, EBV can cause its
host cells to divide uncontrollably -- causing a tumor to develop.

The causes for the transition of EBV from the quiescent phase to an
active mode -- particularly with respect to the responsible factors and
to how the molecular mechanisms function -- have until now remained
elusive. With their findings, the scientists at Helmholtz Zentrum
M�nchen have discovered how the virus terminates latency and activates
its synthesis in the infected cells.

Professor Wolfgang Hammerschmidt, head of the Department of Gene Vectors
at Helmholtz Zentrum M�nchen, explained: "We have now identified the
crucial function of the viral BZLF1 protein: It activates the genes of
EBV, which are essential for the proliferation of virus particles."
About 70 different genes are switched off during the latent phase
because certain DNA segments are chemically modified: Some DNA building
blocks carry methyl groups. They are a kind of stop signal for the cell
apparatus, so that these genes cannot be converted into protein.

"BZLF1 can detect these methylation patterns in the DNA," said Markus
Kalla, lead author of the study. With its DNA binding domain, the
protein binds directly to the methylated DNA sequence. A second domain
of BZLF1 is responsible for the reactivation of the gene. "Such a
mechanism was not known before," Wolfgang Hammerschmidt said. Previous
research assumed that the methyl groups had to be removed from the DNA
building blocks before the transcription factors could bind to the
regulatory DNA sequence and thus activate the gene.

The researchers' findings indicate that BZLF1 avoids this hurdle.
Accordingly, BZLF1 appears to be essential for establishing and
maintaining latency, but also for escaping from it.

During viral synthesis a large number of new particles are usually
formed within the cell. To achieve this, viruses use large portions of
the cell apparatus, in particular specific proteins and factors. After
progeny synthesis the new viruses are released -- researchers speak of a
lytic cycle. The disadvantage: the viruses thus attract the attention of
the immune system, which then fights against the pathogen and destroys
the cell supporting viral synthesis.

However, the Epstein-Barr virus uses another strategy. Instead of
putting all of its energy into immediate synthesis of progeny in the
infected cell, it goes into a resting phase following the infection and
thus prevents a reaction of the immune system. The virus infects cells
of the immune system -- the so-called B cells -- first inserting its DNA
into their cell nucleus. Whereas most viruses immediately start their
lytic proliferation cycle and thus use the cell apparatus to replicate
the DNA and to generate important structural proteins from the genes,
EBV drives transformation of merely a few genes from the cell into
proteins. These so-called latent genes are important for the quiescent
phase: They see to it that the DNA of the Epstein-Barr virus remains
stable in the cell nucleus while the cell itself proliferates. This
seemingly peaceful co-existence ends when the virus goes into the lytic
phase or induces tumor growth.

These findings published in PNAS by Wolfgang Hammerschmidt and his
colleagues constitute an important step for a better understanding of
the role of EBV in tumor growth.
------------------------------------------------------------------------

Story Source:

Adapted from materials provided by Helmholtz Zentrum Muenchen - German
Research Centre for Environmental Health.

------------------------------------------------------------------------

Journal Reference:

1. Kalla, M, Schmeinck, A, Bergbauer, M, Pich, D, Hammerschmidt, W. AP-1
homolog BZLF1 of Epstein-Barr virus has two essential functions
dependent on the epigenetic state of the viral genome. Proceedings of
the National Academy of Sciences, 2010; 107 (2): 850 DOI:
10.1073/pnas.0911948107
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