Wistar Scientists Reveal the Role of a Telomere Capping Complex in Cancer
PHILADELPHIA — (April 10, 2017) — Scientists at The Wistar Institute have unveiled part of the protein complex that protects telomeres—the ends of our chromosomes. The study, published online in Nature Communications, explains how a group of genetic mutations associated with this protein complex contributes to various cancers.
Telomeres are the protective structures at the end of chromosomes and are essential for the faithful replication and protection of our genome. Defects in telomere function can lead to genomic instability in cancer, while the gradual shortening of telomeres is associated with the aging of human cells. A key component of the telomere protecting mechanism is a multi-protein complex called shelterin. Shelterin protects chromosome ends from triggering DNA damage response mechanisms; it also regulates telomere maintenance and replication by the enzyme telomerase.
This new study describes the atomic structure of the protein-protein interaction between two subunits of the shelterin complex, POT1 and TPP1. Several gene mutations have been described as affecting portions of POT1 in familial melanoma, glioma and chronic lymphocytic leukemia. Based on a host of structural, biochemical and cell-based data, the study explains how these mutations may contribute to malignant transformation.
“Our research adds a piece of the puzzle toward solving the intricate structure of the shelterin complex, a fundamental player in the maintenance of telomere DNA integrity,” said Emmanuel Skordalakes, Ph.D., Associate Professor in the Gene Expression and Regulation Program at Wistar and lead author of the paper. “Based on our data, we suggest that the cancer-associated mutations reported in POT1 affect the integrity of telomeres, leading to chromosomal abnormalities and in turn genomic instability, which is a hallmark of cancer progression. We think that this mechanism works in combination with other fundamental genetic defects characteristic of these malignancies.”
The Skordalakes lab used x-ray crystallography to reveal the structure of the POT1-TPP1 complex. The structure was used as a platform to design biochemical and cell-based assays to study the effect of several mutations on this structure. They found that some of these mutations reduce the affinity between the two proteins and, consequently, their ability to bind to telomeric DNA efficiently, whereas others perturb the POT1 structure. They also used imaging techniques to look at different aspects of chromosomes and telomeres and found that these mutations result in defects in telomere length and structure, such as fragile telomeres that tend to break during replication stress, missing telomeres and chromosome fusion between telomeres from two different chromosomes.
This study sheds light on the mechanism by which these cancer-related genetic mutations affect telomere stability, and further research will be necessary to better understand their precise function and how it relates to cancer.
This work was supported by National Institute of General Medical Sciences grant R01 GM088332, National Cancer Institute grant R01 CA201312, the US Department of Energy grants No. DE-AC02-76SF00515 and DE-AC02-05CH11231 and the National Institutes of Health grant P41GM103393. Core support for The Wistar Institute was provided by the Cancer Center Support Grant P30 CA010815.
Co-authors of this study from The Wistar Institute include: Cory Rice, Prashanth Krishna Shastrula, Andrew V. Kossenkov, Robert Hills, Louise C. Showe and Susan Janicki. Other co-authors include: Duncan M. Baird from Cardiff University, United Kingdom and Tzanko Doukov from Stanford University.
This study has been recommended in F1000Prime as being of special significance in its field.
The Wistar Institute is an international leader in biomedical research with special expertise in cancer research and vaccine development. Founded in 1892 as the first independent nonprofit biomedical research institute in the United States, Wistar has held the prestigious Cancer Center designation from the National Cancer Institute since 1972. The Institute works actively to ensure that research advances move from the laboratory to the clinic as quickly as possible. wistar.org.