Ribosome finding could help fight cancer

Ribosome with its changes in
position color-coded, ranging from
blue—indicating no movement—to
red, indicating large movements
Credit: UC Berkeley

Scientists say they have identified a series of intricate biochemical steps that lead to the successful production of proteins.

Their study, published in Cell, revealed a “quality control” test process for ribosome assembly.

And since there are well-established links between defects in ribosome assembly and cancer, the group’s findings could have implications for the development of new anticancer therapies.

“With important cellular machines like ribosomes, it makes sense that some process exists to make sure things work correctly,” said senior study author Katrin Karbstein, PhD, of The Scripps Research Institute in Jupiter, Florida. 

“We’ve shown that such a quality control function exists for ribosomal subunits that use the system to do a test run but don’t produce a protein. If the subunits don’t pass, there are mechanisms to discard them.”

As part of the translation stage of protein biosynthesis, the ribosome decodes information carried in messenger RNA (mRNA) to produce a protein.

To produce mature, functioning ribosomal RNAs (rRNAs), the body first makes precursor rRNAs that can be processed into mature ones. In human cells, this is done in 2 stages—the first occurs in the nucleolus and the second in the cytoplasm.

In the cytoplasm, these pre-mature ribosomal subunits encounter large pools of mature subunits, mRNA, and numerous assembly factors and translation factors that help complete the process.

During the final maturation process, various assembly factors prevent the translation process from acting on the subunits prematurely. This would result in their rapid degradation or in the production of incorrectly assembled proteins, both with potentially lethal outcomes for the cell.

While the work of these assembly factors explains how premature translation is blocked, their presence raises an important question: Does the conversion of inactive assembly intermediates into mature ribosomes require checkpoints to assure that subunits are functional?

Dr Karbstein and her colleagues were able to show that, during this translation-like cycle, the newly made ribosome subunit initially joins with its complementary pre-existing subunit to form a much larger complex through the influence of a single translation factor.

This large ribosome complex contains no mRNA, which is blocked by assembly factors, and therefore produces no protein. Once the major functions of the smaller ribosome subunit have been inspected and approved, another translation factor breaks up the complex and actual protein production occurs.

“What is important here is that the test cycle involves the same translational factors that are involved in normal translation,” Dr Karbstein said. “It’s the most elegant and efficient way to produce perfect ribosomes.”

Interestingly, the researchers noted, the majority of assembly factors involved in this translation-like test cycle are conserved in creatures ranging from one-celled organisms to humans, suggesting that this evolutionary mechanism is common to all.

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