December 26, 2016 | David F. Coppedge

Small Molecules Play Key Roles in Cells

Molecular biologists are finding a universe of functional small proteins and RNAs that were considered junk or not even known to exist.

We often hear that 98% of the human genome is “noncoding” for proteins. This may be a very misleading statistic. Actually, most of the genome is transcribed into RNAs, whether or not those result in the large proteins we know about. Hidden in those transcripts are small molecules known as micro-RNAs, and some longer ones known as “long non-coding RNAs” (lncRNAs) that are increasingly seen as vital in gene regulation. And now, scientists are beginning to uncover transcripts that are translated into protein fragments. Too small to be called proteins, these polypeptides also play vital roles in cell health. The genes that program these small molecules, once dismissed as “junk DNA,” are revealing more sophistication in the genome than previously thought.

Research reveals the importance of long non-coding RNA regulating cellular processes (Beth Israel Deaconess Medical Center). This article expressly dismisses the “junk” label for lncRNAs. They found something when they went looking through the genetic junkpile:

Long non-coding RNAs appear to be transcribed from our DNA in a similar manner to coding messenger RNAs but are not translated into proteins. While lncRNA molecules do not produce correspondingly lengthy proteins, researchers have wondered whether some of these molecules may contain segments of sequences that can code for very short proteins, or polypeptides.

“Whether such small, hidden polypeptides are actually functional, or represent ‘translational noise’ within the cell is still relatively unclear,” said senior author Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Center and Cancer Research Institute at BIDMC. “Our team set about trying to understand to what extent lncRNA molecules might actually encode functional polypeptides, and how important such peptides might be.

The scientists discovered an important role for a 90-base long lncRNA transcript that produces a polypeptide known as SPAR (Small regulatory Polypeptide of Amino acid Response). This small protein, they found, plays “an important role in modulating the activity of the mTORC1 protein complex, which is a critical sensor of nutrient availability within cells.” The mTORC1 protein is a key target for understanding cancer’s unregulated growth. Since this lncRNA is highly expressed in a number of cell types, including muscle, they determined that it plays an important role in muscle repair after injury. It may also fine-tune the mTORC1 complex for different tissue types. Finding roles for small proteins will probably lead to more discoveries, ratcheting down that “98% non-coding” statistic:

The results suggest that lncRNAs may have diverse roles and functions. Although they may not code for large proteins, lncRNAs may produce small polypeptides that can fine tune the activity of critical cellular components. The findings also expand the repertoire of peptide-coding genes in the human genome that should be studied and annotated.

Small but mighty: Tiny proteins with big roles in biology ( This article adds to the growing realization that small polypeptides or “microproteins” exist throughout the cell that have been ignored before now.

We all know how hard it is to find something small like a dropped contact lens that blends into the background. It’s similarly tough for biologists to find tiny proteins against the complex background of the cell. But, increasingly, scientists are learning that such microproteins, which are overlooked by traditional detection methods, also have important biological roles to play.

Using a new microprotein detection strategy, Salk scientists discovered a human microprotein involved in one of the cells’ key housekeeping tasks: clearing out genetic material that’s no longer needed. The new molecule could provide a better understanding of how the levels of genes, including disease genes, are controlled in the cell.

One of the Salk researchers says that this points out “blind spots” in our knowledge of the cell. There are things hidden in plain sight. “You can sequence the whole human genome and never know a protein, like this one, was there because it’s too short and falls below the usual length requirement for gene assignment algorithms.” We mentioned the “NoBody” small protein in the 12/12/16 entry.

Small RNAs interact with newly synthesized transcripts to silence chromatin ( Researchers in Germany investigated a “fundamental question” that puzzled them for a decade: what role do small RNA transcripts play in regulating the formation of chromatin? It’s becoming clear that some RNAs work on other RNAs instead of DNA. Specifically, small interfering RNAs (siRNA) can interact with nascent RNA transcripts to induce heterochromatin formation. Chromatin is a protein complex around which DNA is wrapped, affecting the availability of genes for transcription. In addition, chromatin contains histone “tags” that regulate how genes are expressed. This article sheds light on how small RNA and protein pieces interact in this complex regulatory dance.

How repair protein finds DNA damage: Like a first responder, protein quickly scans for damage and slows down to flag DNA repair machinery (Science Daily): This article reveals proteins that do triage before the paramedics arrive, so to speak.

BM-AmazingFacts-cell“Rad4 is like the cop who is the first responder at an accident,” said senior author Bennett Van Houten, Ph.D., Richard M. Cyert Professor of Molecular Oncology, Pitt School of Medicine, and co-leader of UPCI’s Molecular and Cellular Cancer Biology Program. “The cop can move quickly to recognize where the incident is, and regulate traffic while directing the paramedics arriving in an ambulance.”

In other words, RAD4 doesn’t do the surgery, but speeds along the DNA with the ability to recognize where the surgeon needs to work. It’s hard for the researchers to avoid anthropomorphic terms for these smart molecules:

When structural damage is confirmed, Rad4-Rad23 stays near the scene and flags down the ‘paramedics,’ comprising the rest of the DNA repair machinery, to fix the damage. This mechanism, which Dr. Van Houten calls ‘recognition-at-a-distance,’ allows Rad4 to be near the error without impeding the rest of the DNA repair crew.

The old “junk DNA” myth continues eroding. Molecular biologists are seeing, more and more, that even the major league players (proteins and genes) can’t play the game without the bat boys, base sweepers, groundskeepers and other assistants who keep the field in good condition.

Did the big proteins evolve from the microproteins? Only in Darwinian dreams. What use is a base sweeper without a pitcher, batter, catcher, umpire, and manager? A robotic base sweeper can sweep home plate for a billion years and nothing more will happen. What we see here is a finely-coordinated system of large and small players working together on a common goal: running a smooth operation that allows the batter to run the bases.

Intelligent design predicted this. Unguided evolution predicted junk DNA and vestigial organs. If the ability to make predictions matters in science, which position should gain the ascendancy now?

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