Highlights

Above

The ends of chromosomes are protected by caps called telomeres.

© Stocktrek Images

Uncapping a new therapy

19 Dec 2018

A deeper understanding of chromosome capping could improve therapies for both cancer and aging

Switching off the enzyme that adds protective caps to chromosome ends could help fight many types of cancer, A*STAR researchers have shown. The team demonstrated the treatment’s potential by using it to thwart tumor growth in mice.

The zipper style of DNA replication means that the tips of chromosomes cannot be copied, leaving them slightly shorter with each cell division. To prevent loss of genetic information, chromosome ends are protected by caps called telomeres — repetitive, gene-free regions (see image). Each division shortens the telomeres, until they disappear and the cell can no longer divide. In cells that need to divide indefinitely, such as stem cells, an enzyme called telomerase extends telomeres, allowing cells to keep dividing.

However, cancer cells can hijack telomerase, and in non-stem, or somatic, cells, repressing telomerase is an important cancer prevention mechanism.

Telomerase has been well-studied, and yet the suppression mechanism was unknown. Knowing that telomerase is almost identical in humans and mice, but telomerase is not suppressed in mice, Shang Li, a lead author of the study, and colleagues, located two genetic switches distant from the telomerase gene.

Prabha Sampath’s team at A*STAR.

© 2018 A*STAR Institute of Medical Biology

They found that a master regulator of development, HOXC5, and the microRNA mir-615-3p, which is nested inside the HOXC5 gene, act together to suppress telomerase through these distant switches. Further study showed that the switches are present in many long-lived mammals, including humans and chimpanzees, but not in short-lived mammals, like mice and rats, as an extra barrier against the increased tumor risk that accompanies a longer lifespan.

To confirm their hypothesis, the team artificially increased HOXC5 and mir-615-3p in tumor cells introduced into mice. Tumor growth was strongly inhibited, thanks to suppression of telomere extension; telomeres shortened rapidly and cell division was disrupted.

“This study is a classic example of how a protein-coding gene, HOXC5 and its associated microRNA, together control the expression of [telomerase] and failure of this mechanism can contribute to cancer progression,” says Prabha Sampath, of the A*STAR Institute of Medical Biology, Singapore.

Shang Li’s group at The National University of Singapore.

© 2018 Shang Li, NUS

Telomerase is involved in over 85 per cent of human cancers, which means telomerase-specific treatments could have broad applications.

Interestingly, the findings also have implications for aging, since “limiting the cell proliferation capacity of somatic cells eventually leads to aging,” says Li. The team now aims to find other genetic elements involved in silencing telomerase during healthy stem cell differentiation. “Identifying these factors will provide the possibility of either activating telomerase for anti-aging therapy or inhibiting telomerase for cancer therapy.”

The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore (GIS), the Institute of Medical Biology (IMB), the Institute of Molecular and Cell Biology (IMCB), and the Bioprocessing Technology Institute (BTI).  For more information about the team’s research, please visit the Shang Li group webpage.

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References

Yan, T. D., Ooi, W. F., Qamra, A., Cheung, A., Ma, D. L., et al. HoxC5 and miR-615-3p target newly evolved genomic regions to repress hTERT and inhibit tumorigenesis. Nature Communications 9, 100 (2018).  | article

About the Researchers

Dr. Sampath joined the Institute of Medical Biology, Singapore to set up her own research group in May 2008. She is now a Senior Principal Investigator at IMB, holds an adjunct position at Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore and Duke-NUS School of Medicine. Currently working on translation control of gene expression in multiple systems, Dr. Sampath’s projects are focused on identification of specific novel therapeutic targets.

Dr Li is an Associate Professor at the Duke-NUS Medical School. His research interests include the regulation of telomerase activity by post-translational modification of telomerase and telomerase-related factors, and the transcriptional regulation of human telomerase reverse transcriptase.

This article was made for A*STAR Research by Nature Research Custom Media, part of Springer Nature