Flash mob in the nucleus
Study clarifies why some proteins 'flock together' in the nucleus

Date:
June 22, 2021
Source:
University of Bonn
Summary:
The nucleus is much more than a storage compartment for chromosomes:
It also contains the complex machinery producing transcripts of
the genes that are currently needed and releases them into the
cell body. Some of the proteins involved herein are not evenly
distributed in the nucleus, but cluster at specific sites. A study
now shows how these 'flash mobs' are regulated.



FULL STORY ========================================================================== Almost all cells in our body contain a nucleus: a somewhat spherical
structure that is separated from the rest of the cell by a membrane. Each nucleus contains all the genetic information of the human being. So
it serves as a kind of library -- but one with strict requirements: If
the cell needs the building instructions for a protein, it won't simply
borrow the original information.

Instead, a transcript of it is made in the nucleus.


==========================================================================
The machinery required for this is very complex, not least because the transcripts are not simple copies. In addition to essential information,
genes also contain numerous passages of meaningless "garbage." They
are removed when the transcript is made. Biologists call this editorial revision "splicing." "An important role in splicing is played by the SMN complex, a 'molecular machine' consisting of nine different proteins,"
explains Prof. Dr. Oliver Gruss from the Institute of Genetics at
the University of Bonn, who is also a member of the university's transdisciplinary research area "Life and Health." "Interestingly,
these machines are not evenly distributed in the nucleus.

Instead, they accumulate at specific sites called Cajal bodies." However,
there are no transport mechanisms in the cell nucleus that bring the SMN complexes to Cajal bodies. Instead, the SMN proteins themselves have
certain properties that are responsible for their aggregation. Which
ones these are, was unclear until now.

SMN complexes carry an unusually large number of phosphate groups SMN
complexes have a prominent feature: They carry an unusually large number
of phosphate groups, which are small molecular residues with a phosphorus
atom in the center. "We suspected that this phosphorylation promotes their
mass clustering into Cajal bodies," explains Dr. Maximilian Schilling
from the research group around Oliver Gruss.

Phosphate groups are not part of the actual blueprint of a protein --
they are added later and can also be removed again. This is often how
the cell regulates the activity of the respective protein. The phosphate
group is attached in this process by certain enzymes, the kinases. "We
have now inhibited each of the hundreds of human kinases individually and looked at how that affects the formation of Cajal bodies," Schilling says.

In this way, they encountered a network of kinases, which, when inhibited, caused the Cajal bodies to largely disappear. Further analyses showed
that in the absence of these kinases, phosphorylation of SMN complexes
at specific sites decreased sharply. This then causes the flash mobs
in the nucleus to cease -- the Cajal bodies disintegrate. The finding
is particularly interesting because the kinases identified not only
regulate splicing, but also the translation of the gene transcripts
edited in this way into proteins. These are therefore enzymes that are
crucial for various steps in this vital process.

Mutation causes severe disease The SMN complex is known to human
geneticists not only for its role in splicing: Individual mutations in
its blueprint result in a serious disease, spinal muscular atrophy,
in those affected. One in about 6,000 newborns is born with this
genetic defect. Treatment is extremely expensive; the cost per
patient runs into millions. "Some of the gene defects that cause
spinal muscular atrophy are near the phosphorylation sites of the
SMN complex," explains Gruss. "Affected individuals may therefore
have impaired attachment of phosphate groups to these sites, and
consequently also impaired formation of Cajal bodies. We suspect that
this causes splicing to be impaired, which subsequently results in
the disease symptoms." The kinases identified may therefore also
be suitable as a starting point for new therapies. Preliminary
results from mouse model cells for human spinal muscular atrophy
show that agents that increase kinase activity also improve Cajal
body formation. "It is completely unclear whether these agents also
ameliorate pathological changes in a complex organism," cautions
Gruss against inflated expectations. "That new treatment options will eventually emerge from this is therefore still speculation at this stage." ========================================================================== Story Source: Materials provided by University_of_Bonn. Note: Content
may be edited for style and length.


========================================================================== Journal Reference:
1. Maximilian Schilling, Archana B. Prusty, Bjo"rn Boysen, Felix S.

Oppermann, Yannick L. Riedel, Alma Husedzinovic, Homa Rasouli,
Angelika Ko"nig, Pradhipa Ramanathan, Ju"rgen Reymann, Holger
Erfle, Henrik Daub, Utz Fischer, Oliver J. Gruss. TOR signaling
regulates liquid phase separation of the SMN complex governing
snRNP biogenesis. Cell Reports, 2021; 35 (12): 109277 DOI:
10.1016/j.celrep.2021.109277 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/06/210622142832.htm

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