Journal News

Biochemists identify cause of rare disease

Finding that a mutation in a DNA-replication protein causes the ataxia-like condition has immediate impact on patient care
Marissa Locke Rottinghaus
May 5, 2023

A recent study published in the Journal of Biological Chemistry led to the discovery of the genetic origin of a rare disorder in children.

The condition is known as PARD, which is short for PCNA-Associated DNA Repair Disorder, and it was only identified in 2014. The disease causes intellectual disabilities, accelerated aging, extreme photosensitivity, deafness and more. The mutation identified in this study is only the second to ever be described.

PCNA stands for proliferating cell nuclear antigen, a protein that slides on DNA and promotes DNA repair and replication. The team of researchers led by Brian Kelch, an associate professor of biochemistry and biotechnology at the University of Massachusetts Chan Medical School, determined that PARD may be caused by a mutation in PCNA that causes it to be unstable at high temperatures.

This cartoon of the PCNA life cycle is a figure in the paper "A thermosensitive PCNA allele underlies an ataxia-telangiectasia-like disorder."

The team began investigating this protein and its role in PARD after receiving a phone call from Alexander Jorge, an associate professor of medicine at the University of São Paulo, Brazil, who diagnosed and sequenced the genomes of three unrelated patients with PARD in his clinic. The patients all had an identical PCNA mutation, known as C148S, but it was unclear why this mutation caused such severe disease.

“PCNA performs so many different roles in the cell during DNA replication, DNA repair, cell cycle and chromatin assembly,” Joe Magrino, a graduate student at UMass and lead author on the study, said. “PCNA is called the ‘maestro of DNA replication’ because it plays a central role in coordinating the copying of DNA with other aspects of normal cellular behavior, such as repairing damaged DNA and determining when a cell divides.”

Kelch likened the shape of PCNA to a doughnut and said it clamps onto DNA to perform its normal duties inside the cell.

Rendering by Leonora Martinez-Nunez
The C148S PCNA mutant causes it to be unstable at human body temperature and fall off DNA easily.

“The fact that PCNA is shaped like a ring or a doughnut is absolutely central to its function, because its job is essentially tethering other things to DNA,” Kelch said. “So, its ability to stay on DNA is critically important.”

To figure out the mutation’s impact, the team solved its structure and performed a variety of biochemistry experiments to see how well PCNA bound to DNA in different situations.

“We showed that the new variant discovered in Brazil disrupts the stability of the protein, making it less stable,” Kelch said. “This appears to make it fall off DNA more easily.”

Magrino added: “Our data also suggest that the amount of time PCNA spends on DNA is in a Goldilocks zone. The time can’t be too long or too short and needs to be just right to perform its function.”

In addition, the team observed that the PCNA mutant was extremely sensitive to high temperatures and becomes unstable around normal human body temperature.

“The mutant PCNA functions like a normal protein at room temperature,” Magrino said. “But, if I heat it up to human body temperature, the mutants have profound stability defects that cause them to fail as functional proteins.” 

Even though the team studies molecular biochemistry, these findings had an immediate impact on the PARD patients’ care.

“Because we found that PCNA proteins that have the PARD mutations are sensitive to heat, our physician colleagues are now very cognizant of body temperature of PARD patients and are proactively treating them when they run a fever,” Kelch said.

The team is currently working on designing new techniques to visualize the mutant PCNA bound to DNA. These efforts have proved difficult because they are the first to attempt this goal. Kelch said these experiments and others could help them predict which other mutations in PCNA might lead to PARD.

In addition to benefiting patients with PARD and PARD-like diseases, Kelch and Magrino’s work might someday have implications for cancer treatment because it coordinates the action of numerous proteins that are commonly mutated in cancer patients.

“We know that there's another protein complex, called ATAD5, that works to remove PCNA from DNA,” Kelch said. “I think that PCNA is important for all sorts of diseases, including cancer. So, this is going to be a really important avenue of investigation in the immediate future.”

Enjoy reading ASBMB Today?

Become a member to receive the print edition four times a year and the digital edition monthly.

Learn more
Marissa Locke Rottinghaus

Marissa Locke Rottinghaus is the Editorial Content Manager for ASBMB.

Related articles

Finding a way to combat long COVID
Marissa Locke Rottinghaus
Peering into ocular waste recycling
Marissa Locke Rottinghaus
From the journals: June/July 2019
Courtney Chandler, Isha Dey & Jonathan Griffin
From the journals: March 2019
John Arnst, Courtney Chandler, Isha Dey & Catherine Goodman

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in Science

Science highlights or most popular articles

Meet Shannon Reilly
Profile

Meet Shannon Reilly

May 12, 2025

The JLR junior associate editor discusses the role of adipocytes in obesity at Weill Cornell Medical School.

Meet Donita Brady
Interview

Meet Donita Brady

May 8, 2025

Donita Brady is an associate professor of cancer biology and an associate editor of the Journal of Biological Chemistry, who studies metalloallostery in cancer.

Glyco get-together exploring health and disease
Interview

Glyco get-together exploring health and disease

May 7, 2025

Meet the co-chairs of the 2025 ASBMB meeting on O-GlcNAcylation to be held July 10–13, 2025, in Durham, North Carolina. Learn about the latest in the field and meet families affected by diseases associated with this pathway.

Targeting toxins to treat whooping cough
Journal News

Targeting toxins to treat whooping cough

May 1, 2025

Scientists find that liver protein inhibits of pertussis toxin, offering a potential new treatment for bacterial respiratory disease. Read more about this recent study from the Journal of Biological Chemistry.

Elusive zebrafish enzyme in lipid secretion
Journal News

Elusive zebrafish enzyme in lipid secretion

May 1, 2025

Scientists discover that triacylglycerol synthesis enzyme drives lipoproteins secretion rather than lipid droplet storage. Read more about this recent study from the Journal of Biological Chemistry.

Scientists identify pan-cancer biomarkers
Journal News

Scientists identify pan-cancer biomarkers

April 30, 2025

Researchers analyze protein and RNA data across 13 cancer types to find similarities that could improve cancer staging, prognosis and treatment strategies. Read about this recent article published in Molecular & Cellular Proteomics.