Three-layered control of mRNA tails

Date:
August 13, 2021
Source:
Aarhus University
Summary:
Researchers have characterized how the essential mRNA poly(A) tails
are synthesized in the budding yeast Saccharomyces cerevisiae. The
study reveals several mechanisms controlling poly(A) tail lengths
and hereby ensuring the robustness of gene expression.



FULL STORY ==========================================================================
In a joint collaboration, researchers from Aarhus, Cambridge and Warsaw
have characterized how the essential mRNA poly(A) tails are synthesized
in the budding yeast Saccharomyces cerevisiae. The study reveals several mechanisms controlling poly(A) tail lengths and hereby ensuring the
robustness of gene expression.


==========================================================================
As their name suggests, messenger RNAs (mRNAs) act as intermediary
molecules in the transfer of genetic information from DNA to their
translation into proteins. In eukaryotic organisms, including humans,
plants and fungi, the 'back end' of the mRNA molecule almost invariably
carries a tag of repeated units of adenosines, or As, one of the four
alphabets in the genetic code. This unique structure, the poly(A) tail,
is essential for the mRNA to get through the cell nucleus to the ribosomes located in the cytoplasm where protein synthesis occurs.

The poly(A) tail is a dynamic structure, which gets shorter over
time as the mRNA molecule ages. Indeed, removal of the poly(A) tail by cytoplasmic enzymes is believed to work as a timer, or a fuse, triggering
mRNA degradation once all the As have been removed. This in turn provides
for cellular mRNA homeostasis ensuring that the right amount of template
is available for the ribosomes.

For such a system to operate efficiently, poly(A) tails must have a
precise length when they enter the cytoplasm and, consequently, when they
are made in the nucleus. Indeed, this is the case, with species-specific poly(A) tail lengths varying from ~60 As in single-celled fungi to ~250
As in human cells.

However, the instructions to make poly(A) tails are not encoded in the
DNA sequence together with the rest of the mRNA; instead a dedicated
molecular machinery, called the 'Cleavage and Polyadenylation Factor
(CPF)', adds poly(A) tails to newly produced mRNAs with the help from
accessory factors. But how then is precise poly(A) tail length achieved
when it is not instructed by the DNA? The researchers revealed a
surprising finding In the new study, published in the journal Genes & Development, researchers from Aarhus, Cambridge and Warsaw revealed the surprising finding that more than one pathway serves to control poly(A)
tail lengths in Saccharomyces cerevisiae, a single-celled yeast widely
known for its use in baking and brewing, but also an invaluable workhorse organism in molecular biology laboratories worldwide.

Initially, perturbations of individual pathways suspected to regulate
poly(A) tail synthesis yielded little effects on tail length, implying
the presence of redundant mechanisms. Indeed, careful manipulation of
different accessory factors led to the realization that three separate mechanisms control poly(A) tail lengths. Two of these are executed
by so-called 'poly(A) binding proteins (PABPs)', which associate
with nuclear mRNA poly(A) tails and instruct the CPF machinery to
terminate its tail synthesis. The third of the identified pathways was particularly unexpected as it does not require PABPs at all but instead
takes advantage of an in-built property of the CPF machinery itself to
cease A addition. In the absence of all three control systems poly(A)
tails grow excessively long, severely compromising protein production.

The current study provides an example of how critical processes in
nature often have -- sometimes several -- backup systems. In the case
of poly(A) tail synthesis, such 'fail-safe' mechanisms have likely
evolved to compensate for natural fluctuations in the availability of
PABPs. Providing alternative biochemical pathways therefore ensures that
the transfer of genetic information does not come to a halt if one factor temporarily becomes limiting.

The scientific article was published in
the international journal Genes & Development: ========================================================================== Story Source: Materials provided by Aarhus_University. Original written
by Lisbeth Heilesen.

Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Matti Turtola, M. Cemre Manav, Ananthanarayanan Kumar, Agnieszka
Tudek,
Seweryn Mroczek, Paweł S. Krawczyk, Andrzej Dziembowski,
Manfred Schmid, Lori A. Passmore, Ana Casan~al, Torben Heick
Jensen. Three- layered control of mRNA poly(A) tail synthesis
in Saccharomyces cerevisiae. Genes & Development, 2021; DOI:
10.1101/gad.348634.121 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/08/210813152009.htm

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