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Atomic-scale simulations unravel evasion of cancer-causing molecules

Nuclear Excision Repair of a polycyclic aromatic hydrocarbon-derived lesion in DNA on the left. Image courtesy Yuqin Cai.

Powerful cancer-causing molecules, polycyclic aromatic hydrocarbons (PAH), are inhaled by people through automobile exhausts, are present in cigarette smoke, and are part of any barbequed meal. Once ingested or inhaled, these big, bulky multi-ringed molecules are converted into reactive carcinogenic compounds that can bind to DNA, sometimes literally bending the double helix out of its normal shape, to form damaged areas called lesions, eventually causing cancer-initiating mutations.

The body’s DNA repair system -- nuclear excision repair (NER) -- fixes PAH lesion damage by removing the segment of DNA where the lesion is bound and patching up the resulting gap. But, some lesions are especially resistant, making them much more likely to cause mutations. Now, a research team at New York University, US, has gained new insight with atomic-scale supercomputer simulations of the ability of certain PAH-derived lesions to evade the DNA repair machinery, which could help preventative medicine and cancer treatment.  

They found that some lesions stabilize the DNA they damage, making it difficult for a repair protein to mark the lesion for repair. Their research was published earlier this year in the journal Biochemistry. More recent articles about NER of DNA lesions from the same group appeared in Nucleic Acids Researchthis summer.

Stopping the signal for repair

Stability of the DNA double helix is a key feature that determines whether DNA is flagged for repair in the first place by a protein called XPC.

"Some lesions cause DNA to be locally destabilized, but there are lesions that actually stabilize the DNA so that the two strands come apart with great difficulty," says Suse Broyde, a biology professor at NYU, who specializes in providing a mechanistic understanding of complex biological processes using molecular dynamics simulations and other computational approaches. "Sometimes they're even more stable than undamaged DNA."

The XPC protein patrols a genome looking for weakened areas. When it finds one, it slips a structure called a beta-hairpin between the strands, marking the DNA for repair. But if a lesion makes DNA more stable, the strands become more difficult to separate and the beta hairpin can't signal for repair.

"Every kind of molecule interacts with other molecules through so-called Van der Waals interactions," says Nicholas Geacintov, a chemistry professor at NYU. "The DNA and the carcinogen bound to it also have the same kind of interactions," he says, referring to the PAH-derived lesions that wedge themselves between DNA base pairs.

Top section: Models show different lesions wedged between DNA bases. Lesions that are more easily repaired, like the one marked in the image, are more likely to be removed before they can create mutations in replicated DNA. Bottom section: The stacking interactions -- or Van der Waals forces -- between lesions and adjacent DNA base pairs stabilize DNA. Dibenzo [a,l] pyrene molecule derived lesions (featured on the top and bottom right) have a great number of interactions, making them especially difficult to remove.

The role of Van der Waals forces was clarified with computer simulations performed, analyzed, interpreted and visualized by Yuqin Cai, a post-doctoral senior research scientist in Broyde's lab. "The computer simulations revealed structural, energetic, and dynamic properties of the DNA containing the PAH-derived lesions," says Broyde.

"You can make movies of the dynamic trajectory which allow you to see the real mobility of the entire system. It's not rigid — you can see its aliveness."

Atomic-level visualizations revealed that of the six different lesions examined, those caused by dibenzo[a,l]pyrene, a type of PAH, were the most resistant to repair. The five-ringed structure of the carcinogen stabilized the DNA much better than the four- and three-ringed structures of the other PAHs.

Knowing which lesions are the most repair resistant could play an important role in preventative medicine; individual people harboring them could be counseled to avoid further exposure, particularly helping smokers.

Making drugs that are less susceptible to NER

"Without experiments they wouldn't have anything to model and without modeling it would be very hard for us to understand what we are measuring," Geacintov says.

Experiments showed the more stable the DNA, the higher the temperature at which it melted. The most stabilizing lesion melted nearly 10 degrees higher than the melting temperature of DNA with no lesions; this lesion was the most repair-resistant and also the most stabilizing.

To compute the raw data (coordinates of structures as a function of time) for the analyses and visualizations, the Longhorn, Lonestar, and Ranger supercomputing resources at the Texas Advanced Computing Center, and other systems in the Extreme Science and Engineering Discovery Environment (XSEDE), were used.

Uncovering the stabilizing properties that allow some lesions to evade NER could help develop better chemotherapeutic drugs. For example, the widely used chemotherapy drug, Cisplatin, attacks the DNA of cancerous cells, interrupting unregulated replication. However, the cell's own NER machinery combats the drug by removing it and repairing the genome.

"One direction in drug design is to find pharmaceuticals that still inhibit replication but that are less susceptible to NER," Broyde says. "Understanding the mechanism of NER will be valuable in designing the next generation of chemotherapeutic agents. These would be more effective if they were more resistant to NER."

A version of this story was originally published on the TACC website.

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