Biological complexity: cleaning up 'bad' molecules (Introduction)

by David Turell , Saturday, June 11, 2022, 15:29 (896 days ago) @ David Turell

How to control molecular garbage:

https://www.sciencedaily.com/releases/2022/06/220609131839.htm

"A prime example is the RNA exosome. RNA molecules perform many roles in cells. Some of them are translated into proteins; others form a cell's protein-building machinery. The RNA exosome is a cellular machine that degrades RNA molecules that are faulty, harmful, or no longer needed. Without this microscopic Marie Kondo to prune what doesn't spark joy, our cells would become dysfunctional hoarders, unable to function.

"'RNA surveillance and degradation pathways exist in all forms of life," explains Christopher Lima, Chair of the Structural Biology Program in the Sloan Kettering Institute. "From bacteria to humans, all living things have mechanisms to monitor the quality of RNA and to purposely degrade it."

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"...it turns out that these degradation pathways are highly regulated and control everything from embryonic development to the progression of the cell cycle.

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"In a new paper published June 9, 2022 in Cell, Dr. Lima and M. Rhyan Puno, a postdoctoral fellow in the Lima lab, present findings that help explain how the RNA exosome locates the RNA that needs to be degraded. With the help of cryogenic-electron microscopy (cryo-EM), an advanced type of imaging technology, the scientists were able to decipher the structure of a protein assembly called Nuclear Exosome Targeting (NEXT) Complex, which is a key part of the degradation machinery.

"'We knew that NEXT targets and delivers RNA to the exosome, but biochemically and structurally, we didn't have a clue what it looks like or how it works," Dr. Puno says.

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"From the cryo-EM pictures, the scientists were able to see that the NEXT proteins form a very flexible dimer -- meaning that two copies of NEXT proteins join together as a functional unit.

"'That was really, really puzzling," Dr. Puno says, noting that dimer formation hasn't been visualized before for these types of proteins.

"From biochemical experiments we performed, we know that dimerization is somehow important for degradation," he continues. "But it's still a mystery to us what role the dimer plays in guiding RNA to the exosome."

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"But defects in RNA degradation pathways also play a role in several types of cancer. In fact, two of the genetic mutations that MSK's genetic testing platform, MSK-IMPACT®, tests for are found in genes related to the RNA exosome pathway, including a protein in NEXT.

"And it's not only messenger RNA that needs proper quality control, Dr. Lima explains.

"'The reality is if you have defective RNA quality-control pathways, your ribosomes don't work, your transfer RNAs don't work, your spliceosomes don't work." The list goes on and on.

"The breadth of functions that RNA performs explains why defective RNA degradation pathways can have such cascading disease-causing effects.

"Making sense of these effects will require a deeper and more extensive understanding of not just the RNA exosome itself, but also the "upstream" proteins, like NEXT, that help surveil RNA and decide when an RNA is defective or no longer needed."

Comment: the biochemistry of life comes with required quality controls Ju st like feedback loops stabilize output of processes, garbage molecules must be destroyed, to avoid clogging up the cells. Another example of irrreducible complexity. A cell cannot be designed to produce a product and not have this mechanism also it place. A designer is required.