Scientists find key mechanism linking DNA replication to cancer

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In a breakthrough study, researchers from The Institute of Cancer Research, London, have delved into how tiny alterations in DNA structures might be instrumental in triggering cancer by interfering with the DNA replication process.

This discovery might pave the way to novel treatments and a more profound understanding of cancer’s onset.

DNA Structures: Understanding the Core of Life

DNA is a fundamental element in our cells, carrying the genetic instructions used in the growth, functioning, development, and reproduction of all known living organisms and many viruses.

Replication is a process where DNA makes a copy of itself, which is essential for cell division. Before a cell divides, its entire genome is copied, ensuring each resulting cell has all necessary genetic information.

In certain conditions, the normal double helix structure of DNA alters, forming unusual secondary structures.

Sequences rich in guanine (G) nucleotides can morph into a G-quadruplex (G4), while those with a surplus of cytosine (C) nucleotides form an intercalated motif (iM).

Both structures have been associated with genetic instability and mutations.

The Experiment: A Closer Look at DNA Replication

In the study published in the EMBO Journal, researchers simulated the DNA replication process using purified replication factors in test tubes.

They focused on G4s and iMs – alternative DNA structures – and through comprehensive experiments discovered that just one G4 or iM structure was enough to pause the replication process, with iMs also causing DNA breakage.

During DNA replication, the DNA unwinds, exposing the nucleotides (DNA building blocks) on each of its two strands.

While in this uncoiled, single-stranded form, DNA can fold into the aforementioned unusual secondary structures, which, as the researchers have found, can disrupt the normal replication process.

The researchers went the extra mile to confirm that these secondary structures, not the nucleotide sequences, were the cause of the disruption.

By intentionally mutating the structures, they observed a significant reduction in replication stalling, reinforcing their initial findings.

Implications: DNA Structures and Cancer Development

When DNA replication is obstructed, the genome can undergo various rearrangements, potentially leading to gene deletion, mutation, or movement, affecting gene expression.

If this impacts cellular processes, it could trigger uncontrolled cell division and potentially give rise to cancer.

In fact, about two-thirds of cancer-driving mutations are speculated to result from errors occurring during DNA replication.

Dr. Gideon Coster, who led the research team, noted that while various factors can drive replication stress, “the most common internal source is the DNA template itself.”

Considering there are hundreds of thousands of G4-forming sequences in the human genome, understanding these sequences and how they induce replication stress is pivotal.

Future Horizons: Guiding Treatment and Discovering New Targets

The findings of this research expand scientists’ understanding of how genome instability, influenced by repetitive and structure-forming DNA sequences, occurs.

Not only relevant to cancer, this knowledge also extends to other conditions like neurodegenerative diseases that are caused by repeat expansions, such as fragile X syndrome and Huntington’s disease.

Researchers are optimistic that understanding DNA replication stress could refine future treatments, potentially allowing healthcare professionals to utilize a patient’s replication stress status to direct treatment decisions. Single-stranded DNA, for instance, might serve as a useful biomarker for diagnosing tumors.

Moreover, the insights gained from understanding how these G4 structures influence DNA stability and replication may highlight new drug targets.

Small molecules that bind to G4s, impacting their stability, may present novel avenues for drug development, while targeting helicases, enzymes that unwind DNA structures, might also be a viable approach.

First author Sophie Williams, a Ph.D. student in the Genome Replication team, highlights that these frequently occurring DNA secondary structures are common mutation points in cancer.

She concludes, “Understanding the drivers of replication stress is essential for developing efficient therapies that target the cellular response to replication stress and DNA damage.”

This research is a significant stride towards comprehending the meticulous details of DNA replication and how its perturbations could potentially lead to cancer, thereby informing the future trajectory of targeted cancer therapy and diagnosis.

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The research findings can be found in The EMBO Journal.

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