Mechanism clarifies DNA puzzle

U. ROCHESTER (US) — Scientists have discovered the purpose of a long-known but little understood DNA element that is unique to primates, including humans and monkeys. The finding offers insight into how genes function.

Though the human genome—all the genes that an individual possesses—was sequenced 10 years ago, the researchers say the new findings are needed in order to make advances in medicine, including changing the way a wide range of diseases are diagnosed, treated, and prevented.

“It’s extremely valuable that we’ve sequenced a large bulk of the human genome, but sequence without function doesn’t get us very far, which is why our finding is so important,” says Lynne Maquat, professor of biochemistry and biophysics at the University of Rochester and lead author of a new study published in the journal Nature.

When genes go awry, diseases, such as cancer, Alzheimer’s, and cystic fibrosis can result. A unique regulatory mechanism could prove to be a valuable treatment target as researchers seek to manipulate gene expression—the conversion of genetic information into proteins that make up the body and perform most life functions—to improve human health.

The newly identified mechanism involves Alu elements, repetitive DNA elements that spread throughout the genome as primates evolved. While scientists have known about the existence of Alu elements for many years, their function, if any, was largely unknown.

Maquat discovered that Alu elements team up with molecules called long noncoding RNAs (lncRNAs) to regulate protein production. They do this by ensuring messenger RNAs (mRNAs), which take genetic instructions from DNA and use it to create proteins, stay on track and create the right number of proteins.

If left unchecked, protein production can spiral out of control, leading to the proliferation or multiplication of cells, which is characteristic of diseases such as cancer.

“Previously, no one knew what Alu elements and long noncoding RNAs did, whether they were junk or if they had any purpose. Now, we’ve shown that they actually have important roles in regulating protein production,” Maquat says.

The expression of genes that call for the development of proteins involves numerous steps, all of which are required to occur in a precise order to achieve the appropriate timing and amount of protein production.

Each of these steps is regulated, and the pathway discovered is one of only a few pathways known to regulate mRNAs directly in the midst of the protein production process.

Regulating mRNAs is one of several ways cells control gene expression, and researchers are honing in on this regulatory landscape in search of new ways to manage and treat disease.

“This new mechanism is really a surprise, Maquat says. “We continue to be amazed by all the different ways mRNAs can be regulated.”

Maquat and graduate student Chenguang Gong, the study’s first author, found that long noncoding RNAs and Alu elements work together to trigger a process known as SMD (Staufen 1-mediated mRNA decay), that conditionally destroys mRNAs after they orchestrate the production of a certain amount of proteins, preventing the creation of excessive, unwanted proteins in the body that can disrupt normal processes and initiate disease.

Specifically, long noncoding RNAs and Alu elements recruit the protein Staufen-1 to bind to numerous mRNAs. Once an mRNA finishes directing a round of protein production, Staufen-1 works with another regulatory protein previously identified by Maquat, UPF1, to initiate the degradation or decay of the mRNA so that it cannot create any more proteins.

While the research fills in a piece of the puzzle as to how genes operate, it also accentuates the overwhelming complexity of how DNA shapes us and the many known and unknown players involved.

The research was supported by a grant from the General Medical Sciences Division of the National Institutes of Health and an Elon Huntington Hooker Graduate Student Fellowship.

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