Scroll Top

A groundbreaking discovery exposes the ‘licensing’ dynamics of DNA replication

dna-g6b2a5a599_1280

A new study led by UNC School of Medicine researchers has shed light on a critical mechanism that happens during cell division and is a potential cause of DNA damage in certain cases, including cancer.

The researchers created a sophisticated experimental framework for researching the process known as “origin licensing,” which they published in Nucleic Acids Research. During cell division, cells employ this mechanism to control, or “license,” the replication of their genomes.

The dynamics of this process were exposed for the first time by the researchers. They demonstrated how these dynamics differ in the two basic states of genomic DNA, the “euchromatin” state, which is relatively loose and open for gene activity, and the “heterochromatin” state, which is wound more tightly to silence gene activity, resulting in different risks of DNA damage during replication.

“Our findings could help explain why certain parts of the genome are more vulnerable to DNA damage during replication in some cancer cells,” said study senior author Jean Cook, PhD, a professor of biochemistry and biophysics at the UNC School of Medicine and a member of the UNC Lineberger Comprehensive Cancer Center.

Origin licensing takes place during the G1 phase of cell replication, which is the first, preparatory phase of cell replication. It entails the use of a variety of enzymes that connect to DNA in chromosomes at specific points where DNA-copying is to occur. The enzymes effectively license DNA copying, ensuring that cells do not duplicate their genomes.

Cook and other scientists have already outlined the fundamental mechanism of origin licensing and identified the proteins involved. However, this work is the first to show in detail how the process develops in cells as they prepare for cell division over time. To achieve this achievement, study first author Liu Mei, PhD, a postdoctoral researcher in the Cook laboratory, used a combination of static and time-lapse microscopic imaging methods.

See also  Climate warming is causing birds to deposit their eggs a month early

Cook described Liu’s work as “very thorough and detailed, a technical tour de force.”

Mei studied the origin licensing process, including the loading of licensing enzymes, in the two primary states of the genome: euchromatin and heterochromatin, as an early demonstration of her experimental platform. She saw a significant change.

“In essence, heterochromatin — more compressed DNA — loads these licensing enzymes very late compared to what we see in more open euchromatin,” Mei said.

At the very least, this results suggested that in dividing cells with an unusually short G1 phase, the highly compressed DNA in the cell genome would never be completely licensed for replication, possibly leading to significant mutations during replication and even cell death. The researchers observed that when they artificially shortened the G1 phase in test cells, heterochromatin parts of the cells’ genomes had considerably more under-replication and DNA damage than euchromatin areas, confirming this theory.

The G1 phase of cells may be reduced for a variety of causes, including cancer. As a result, the research shows that incorrect origin licensing may contribute to “genomic instability,” or the potential for particular cancer types to accumulate more mutations, as well as the genomic sites of that instability.

The work also established the researchers’ experimental platform as a tool for future research on origin licensing dynamics and genomic instability, which might lead to novel cancer treatments in the future.

The National Institutes of Health contributed funding (R01GM102413, R01GM083024, R35GM141833, R01-GM138834).

Related Posts

Leave a comment

You must be logged in to post a comment.