Scientists have identified a gene critical to one of the cell’s most important repair processes.
The gene, known by the acronym ELOF1, prioritizes repairing DNA damage that can interfere with the function of a cell’s genes, a process known as transcription-coupled repair.
In a study recently published in Nature Cell Biology, a research team including Washington State University and Erasmus Medical Center scientists in the Netherlands demonstrates that ELOF1 repairs sun damage and other DNA lesions that would otherwise contribute to aging.
“When cells are damaged by ultraviolet light, it damages our DNA. It is up to our cells to transcribe and repair the DNA damage, but depending on the severity of these lesions, our DNA may be unreadable and irreparable,” said Kathiresan Selvam, a postdoctoral researcher in John Wyrick’s laboratory at WSU, who was co-author on the paper.
Before this latest finding, only three genes were linked to transcription-coupled repair, all of which were identified by genetic mutations in human patients.
ELOF1 and its counterpart in yeast, Elf1, were discovered through collaborative work done by the Jurgen Marteijn laboratory at the Oncode Institute at Erasmus Medical Center and Wyrick’s lab in WSU’s School of Molecular Biosciences. Marteijn’s group uncovered ELOF1 in a genetic experiment known as CRISPR/Cas9 screening. In the meantime, Selvam and colleagues at WSU zeroed in on the yeast counterpart of ELOF1, a gene known as Elf1.
To determine the gene’s significance in DNA repair, Selvam and graduate student Dalton Plummer took cells with and without the gene knocked out and irradiated them with UV light. Two hours later, plenty of time for DNA to heal itself in yeast, Selvam and Plummer isolated the genomic DNA and assessed the damage using a genome-wide sequencing technique developed at WSU’s Pullman campus by Peng Mao, a former associate research professor in the Wyrick lab. On average, yeast cells without Elf1 had a decrease in repair efficiency compared to those cells with the Elf1 gene. Researchers at Erasmus found similar results in human cells.
A key question is whether mutations in ELOF1 contribute to human disease. Given previous research indicating that mouse embryos die without ELOF1, Selvam estimates humans, and potentially other forms of life, may not be able to survive without it. One possibility is that ELOF1 function could somehow be stimulated to help prevent the accumulation of DNA damage in aging cells and potentially treat individuals with Cockayne Syndrome – a rapid aging disease where patients typically don’t survive beyond their teen years.
“ELOF1 is a tiny protein that has been evolutionary conserved over time,” Selvam said. “It’s likely preserving an important role across many domains of life.”