Every cell in the human body faces a chronic challenge: protecting its DNA. Whenever cells divide, their genetic material must be copied accurately. But DNA is continuously under attack, and when damage goes unrepaired, it can threaten genome stability and contribute to the progression of disease.
Now, a new study led by University of Ottawa Faculty of Medicine researchers reveal how a specialized protein helps cells safeguard their genetic material. Published in Science Advances the findings also shed new light on the progression of a rare inherited skeletal disorder by showing how mutations can interfere with the machinery responsible for DNA repair.
"Our DNA is constantly exposed to damage, so cells rely on specialized proteins not only to repair it, but also to recognize where and when that repair is needed," says Dr. Jean-François Couture , co-corresponding author of the study and full professor in the Faculty's Department of Biochemistry, Microbiology and Immunology (BMI ). "Our work shows how even subtle changes that interfere with this recognition can compromise DNA repair, threaten genome stability and, ultimately, contribute to disease."
The work's first author is Dr. Hossein Davarinejad , a postdoctoral fellow in Dr. Couture's lab and the 2024 recipient of the Polanyi Prize in Physiology and Medicine , a prestigious award named after Nobel laureate John Polanyi and sponsored by Ontario's government. Dr. Amélie Fradet-Turcotte at Université Laval is the study's co-corresponding author.
Recognizing the right signals
Inside our cells, DNA is packaged around proteins called histones. These proteins organize genetic material and help regulate how it is accessed. Different versions of histones, known as variants, carry distinct molecular features that other proteins can recognize.
The newly published study shows that chemical changes to a histone variant dubbed H3.1 regulate how it interacts with the TONSL protein (involved in maintaining genome integrity) and that these interactions play an important role in repairing damaged DNA.
The collaborators discovered that these proteins use several molecular binding pockets to recognize histones. Rather than relying on a single point of contact, the pockets essentially work together to interpret multiple chemical signals.
The team also found that two of these pockets recognize specific chemical modifications on H3.1: methylation at one position and acetylation at another. These modifications are associated with regions of DNA involved in regulating genes, offering new insight into how the machinery that protects DNA responds to its molecular surroundings.
Connecting molecular changes to disease
The findings have potentially significant implications for DNA repair and human health.
That's because TONSL helps coordinate DNA repair, particularly when cells prepare to divide. The researchers found that mutations in a region of the protein associated with a disease called sponastrime dysplasia – the ultra-rare inherited skeletal disorder – weaken its ability to recognize H3.1.
In human cells, these altered proteins also failed to restore normal DNA repair function.
"The mutations disrupt the cell's ability to direct DNA repair machinery to damaged DNA as cells prepare for division, allowing DNA damage to accumulate," Dr. Couture explains. "Our findings provide a molecular explanation for how mutations in TONSL may contribute to sponastrime dysplasia and, more broadly, help us understand how defects in DNA repair can lead to human disease."
Ultimately, the team found that when the machinery responsible for recognizing the right molecular signals fails, cells may struggle to repair damaged DNA properly. Over time, this can compromise the stability of genetic information.
Building on earlier discoveries – and expanding the focus
The research builds on the team's earlier work, a groundbreaking 2022 study published in the high-impact journal Science.
Since then, the research team has expanded their investigations through new collaborations that allow them to move beyond isolated proteins and study how these interactions function in living human and mammalian cells.
This approach helps reveal how mutations affect DNA repair in the environment where the process naturally occurs.
According to Drs. Couture and Davarinejad, the team of collaborators next plan to investigate other proteins involved in DNA repair.
"We are interested in expanding our studies to other proteins in DNA repair pathways and to do structural studies with bigger pieces of the puzzle," Dr. Davarinejad says.
Ultimately, the research team is helping to unlock mysteries behind a fundamental principle of cell biology: safeguarding DNA depends not only on repairing damage, but also on ensuring that cells recognize where and when repair is needed.
"Our findings provide a molecular explanation for how mutations in TONSL may contribute to sponastrime dysplasia and, more broadly, help us understand how defects in DNA repair can lead to human disease," Dr. Couture says.
