Researchers identify key complex for ribosome generation
Findings could lead to new treatments for health problems ranging from neurodevelopmental disorders to cancer

Date:
March 29, 2022
Source:
UT Southwestern Medical Center
Summary:
Researchers have identified a four-protein complex that appears to
play a key role in generating ribosomes -- organelles that serve
as protein factories for cells -- as well as a surprising part in
neurodevelopmental disorders. The findings could lead to new ways
to manipulate ribosome production, which could impact a variety
of conditions that affect human health.



FULL STORY ==========================================================================
UT Southwestern researchers have identified a four-protein complex that
appears to play a key role in generating ribosomes -- organelles that
serve as protein factories for cells -- as well as a surprising part in neurodevelopmental disorders. These findings, published in Cell Reports,
could lead to new ways to manipulate ribosome production, which could
impact a variety of conditions that affect human health.


========================================================================== "Ribosomes are fundamental for life, but we've had an incomplete
understanding of how they're put together and how the process of ribosome production is regulated," said lead author Michael Buszczak, Ph.D.,
Professor of Molecular Biology and member of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern. "Our findings shed
significant light on these questions." Dr. Buszczak explained that
ribosomes are present in varying amounts in every cell of every
organism on Earth. Because of their key role as protein producers, he
added, variations from these natural set points can have deleterious consequences. For example, cancer cells tend to increase ribosome
production to boost protein production necessary for unchecked cell
division.

In addition, a group of rare diseases known as ribosomopathies --
characterized by abnormal ribosome production -- manifests with a variety
of symptoms including anemia, craniofacial defects, and intellectual disability.

Although every species has ribosomes, most of what's known about ribosome biogenesis has come from the popular lab model, yeast. The basics of this process are the same for human ribosome biogenesis, Dr. Buszczak said,
but the specifics are not. Consequently, the details that make human
ribosome generation unique have been unknown.

To learn more about this process, Dr. Buszczak, Chunyang Ni, a graduate
student in the Buszczak lab, and their colleagues, including Jun Wu,
Ph.D., Assistant Professor of Molecular Biology at UTSW, started by
developing a technique that prompted old ribosomes to glow red and newly generated ribosomes to glow green.

The researchers used this tool on several different human cell types, confirming different rates of ribosome production in each.

Using the gene editing tool called CRISPR, the researchers inactivated individual genes to identify those that might be key players in ribosome biogenesis. Their search turned up four genes known as CINP, SPATA5L1, C1orf109, and SPATA5. Further research showed that these genes come
together into a complex that strips a placeholder protein from ribosomes
when assembly is almost complete, allowing a different protein to take
its place for ribosome maturation.

Previously, SPATA5's function in cells had been unknown; however,
mutations in this gene have been associated with neurodevelopmental
disorders including microcephaly, hearing loss, epilepsy, and intellectual disability. When the researchers inserted two of these mutations into
cells, causing them to create a mutant SPATA5 protein, the cells couldn't generate the normal level of functional ribosomes -- suggesting that
these neurodevelopmental disorders could stem from ribosome problems.

Dr. Buszczak said that he and his colleagues plan to study why the central nervous system appears to be more sensitive than other cell types to
ribosomal disruptions. He added that these findings could eventually
lead to new treatments for cancer, ribosomopathies, and other conditions affected by over- or under-production of proteins.

This work was supported by grants from the National Institute of General Medical Sciences (GM125812 and GM144043) and funding from the Simmons
Cancer Center.

Other UTSW researchers who contributed to this study include Daniel
A. Schmitz, Jeon Lee, and Krzysztof Paw?owski.

Dr. Buszczak is the E.E. and Greer Garson Fogelson Scholar in Medical
Research.

Dr. Wu is a Virginia Murchison Linthicum Scholar in Medical Research
and a Cancer Prevention and Research Institute of Texas (CPRIT) Scholar.


========================================================================== Story Source: Materials provided by UT_Southwestern_Medical_Center. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Chunyang Ni, Daniel A. Schmitz, Jeon Lee, Krzysztof Pawłowski,
Jun
Wu, Michael Buszczak. Labeling of heterochronic ribosomes
reveals C1ORF109 and SPATA5 control a late step in human
ribosome assembly. Cell Reports, 2022; 38 (13): 110597 DOI:
10.1016/j.celrep.2022.110597 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/03/220329142551.htm

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