Failure of a gene-reading quality-control mechanism called Integrator leaves cells littered with abnormal RNA strands that increase cell stress and may contribute to diseases such as cancer and neurodegeneration, a new study has found.
- By STEPHANIE DUTCHEN
The federally funded research, published April 14 in Cell, is the first to reveal the consequences of such failures. In doing so, it explains some of the symptoms seen in patients with Integrator mutations that have stumped doctors and suggests a path toward treatment.
"Normally you can look at the altered gene activity in patients with a mutation and understand how you get from there to the patient's symptoms. But with Integrator, the gene activity doesn't explain the symptoms," said senior author Karen Adelman, the Edward S. Harkness Professor of Biological Chemistry and Molecular Pharmacology in the Blavatnik Institute at Harvard Medical School.
"We discovered that it's not certain genes causing the symptoms, it's the abundance of poor-quality, incomplete RNAs that are made when Integrator is mutated," she said.
The results call for more attention to incomplete RNAs, which have been generally overlooked in research and medicine.
"I've been studying gene transcription for a long time, and the focus has always been on measuring the amount of mature, full-length RNA made from each gene." Adelman said. "We're proposing that the immature RNA that most studies ignore is the very thing that causes cell stress and damage."
The new work opens the door to better understanding diseases associated not just with Integrator mutations but with other, similar malfunctions in RNA production.
The importance of finishing the gene marathon
Integrator is one of many protein complexes in the cell nucleus that help control which genes can be "read" and ultimately translated into the proteins that perform the functions of life.
Adelman and colleagues - led by first author Apoorva Baluapuri, research fellow in biological chemistry and molecular pharmacology in the Adelman Lab - focused on Integrator because mutations in it have been linked to neurologic and blood disorders, cancers, ciliopathies, developmental abnormalities, and other diseases.
Integrator ensures that the machinery preparing to read a gene sequence can make it all the way to the end of the gene. That can be quite a challenge for very long genes.
"It's like how race officials don't let any random person show up to run the Boston Marathon; they hold time trials to make sure runners can finish," Adelman said.
But sometimes, when there's a mutation in the Integrator complex, machinery that's not up to the task sneaks into the gene.
"It's like letting me start a marathon. It would be okay for a short distance, but I'd never make it to the end," Adelman said.
