Silver Nanoclusters Inhibit DNA Replication

Silver nanoclusters—which could be applied to the treatment of cancer in the future—block an early step of DNA replication, a new study by researchers in the Institute for Cancer Genetics at Columbia University Vagelos College of Physicians and Surgeons and the Herbert Irving Comprehensive Cancer Center has found.

Silver nanoclusters, which contain just a few to tens of atoms, are a more recent addition to the collection of silver nanomaterials, including larger-sized silver nanoparticles.

Because of silver nanoclusters’ unique chemical characteristics, they are used in a wide array of applications, including antimicrobial agents and electronics, and are being investigated for use in cancer imaging and drug delivery.

The new study—led by Yu Tao, PhD, a postdoc in the lab of Jean Gautier, PhD, and Shan Zha, MD, PhD, in collaboration with Kam Leong, PhD—assessed the impact of silver nanoclusters on essential DNA transactions to better understand how these nanoclusters might interfere with cell physiology when introduced into the body.

The results revealed that silver nanoclusters halt DNA replication by binding directly to the minichromosome maintenance protein complex (MCM) and preventing its assembly on chromatin. Without the MCM, which unwinds the two DNA strands, replication cannot start. 

Curiously, other silver materials, including silver nanoparticles, silver nanoprisms, and silver ions, did not affect DNA replication at all.

images of silver nanoclusters and nanoprisms
Transmission electron microscopy images of silver nanoclusters (left) and nanoprisms (right) used in the study. Images from Tao, et al. (2021).

Though previous studies suggest silver ions leached from the nanomaterials can kill cells, “it seems there’s something inherent in the geometry of the silver nanoclusters that’s stopping DNA replication,” says Gautier, professor of genetics & development (in the Institute for Cancer Genetics).

The findings shed light on the way silver nanoclusters may kill cells. Though the experiments were conducted in a cell-free system, preventing DNA replication initiation would prevent cells from proliferating. Gautier and Leong will investigate silver nanoclusters' effect on mammalian cells.

“In the long term, we may be able to harness the toxicity of silver nanoclusters,” Gautier says, “and our study could also serve as a starting point to develop inhibitors of the MCM protein complex for both experimental and therapeutic applications.”

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The study, titled “Inhibition of DNA replication initiation by silver nanoclusters,” was published April 27, 2021, in Nucleic Acids Research.

Shan Zha is the James A. Wolff Associate Professor of Pediatrics and associate professor of pathology & cell biology (in the Institute for Cancer Genetics and Herbert Irving Comprehensive Cancer Center).

Kam Leong is the Samuel Y. Sheng Professor of Biomedical Engineering.

All authors (from Columbia University unless otherwise noted): Yu Tao (now at Sun Yat-sen University, Guangzhou, China), Tomas Aparicio, Mingqiang Li (now at Sun Yat-sen University, Guangzhou, China), Kam W. Leong, Shan Zha, and Jean Gautier.

The research was funded by the U.S. National Institutes of Health (grants R50CA233182, P01CA174653, and R35CA197606); National Natural Science Foundation of China (grants 21907113 and 51903256); and Guangdong Provincial Pearl River Talents Program (2019QN01Y131). Funding for open access charge was provided by National Cancer Institute grant R35CA197606.

The authors declared no conflict of interests.