Corporate Banner
Satellite Banner
Scientific Community
Become a Member | Sign in
Home>News>This Article

It Takes Two to Tangle: Wistar Scientists Further Unravel Telomere Biology

Published: Friday, November 23, 2012
Last Updated: Friday, November 23, 2012
Bookmark and Share
Chromosomes are capped at their ends with special DNA structures called telomeres and an assortment of proteins, which together act as a protective sheath.

Telomeres are maintained through the interactions between an enzyme, telomerase, and several accessory proteins. Researchers at The Wistar Institute have defined the structure of one of these critical proteins in yeast.

Understanding how telomeres keep chromosomes–and by extension, genomes–intact is an area of intense scientific focus in the fields of both aging and cancer. In aging, the DNA of telomeres eventually erodes faster than telomerase and its accessory proteins can maintain it, and cells die. In cancer, tumor cells hijack the process, subverting the natural method by which our bodies limit cell growth; cancer cells, then, can grow and multiply unchecked.

One of these accessory proteins, Cdc13, is integral to telomere maintenance and essential for cell viability in yeast, according to researchers at The Wistar Institute. In a study published in the journal Structure, available online now, a team of scientists led by Emmanuel Skordalakes, Ph.D., an associate professor in The Wistar Institute Cancer Center’s Gene Expression and Regulation Program, has determined how mutations in a particular region of Cdc13 can lead to defects in telomeres that could jeopardize DNA.

Cdc13 normally functions as a matched-set, where two copies of the protein form what is known as a dimer. Skordalakes found that mutations in a region of Cdc13 (called OB2) prevent Cdc13 copies from binding to each other. The findings help explain the biology of this key telomere maintenance protein, and may eventually lead to novel anticancer therapeutic if their findings translate to a similar molecular system used to maintain human telomeres, Skordalakes says.

“If we could target the OB2 region of Cdc13, for example, it would throw a wrench in the works of telomere maintenance,” said Skordalakes. “If you can disrupt recruitment of telomerase in humans, you could potentially drive cells to death.”

Cdc13 serves a dual function in telomere replication. First, it keeps the cells’ natural DNA repair mechanisms from mistaking the telomere for a broken stretch of DNA, which could cause genetic mayhem if such repair proteins fuse the ends of two chromosomes together, for example. Secondly, Cdc13 recruits telomerase and related proteins to place in order to lengthen the telomeres.

In yeast, telomeres are decorated by a multi-protein complex called CST, which contains the proteins Cdc13 (C), Stn1 (S), and Ten1 (T). Cdc13 is a key member of that complex and serves both to cap the telomere structure and recruit key enzymes.

Skordalakes’ newly determined structure demonstrates that, like three of the other four regions of Cdc13, OB2 adopts what is called an oligonucleotide/oligosaccharide-binding fold (OB). These folds normally allow proteins to bind DNA or sugars, but OB2 does neither; its crystal structure indicates that this fold actually forms a large binding surface that helps two Cdc13 proteins to form a dimeric complex.

The authors then used biochemical analyses to determine that OB2 also does not directly bind the protein Stn1. Nevertheless, full-length Cdc13 OB2 mutants deficient in dimerization are also deficient in Stn1 recruitment. When the team inserted strategic Cdc13 mutations into yeast, they found that the cells had abnormally long telomeres, probably as a result of disrupted CST complex assembly caused by impaired Cdc13 dimerization.

“The dimerization of OB2 is required for the proper assembly of the CST complex at the telomeres,” Skordalakes says. “When you disrupt oligomerization of this domain, you disrupt assembly of this complex, and thus regulation of telomere length.”

The study was funded by the Pennsylvania Department of Health, the V Foundation, the Emerald Foundation, the National Institutes of Health, and the National Institute on Aging.

Co-authors include Sandy Harper, David Schultz, Ph.D., and David Speicher, Ph.D., from The Wistar Institute; and Mark Mason, Jennifer Wanat, Ph.D., and F. Brad Johnson, M.D., Ph.D., from the University of Pennsylvania School of Medicine.

Further Information
Access to this exclusive content is for Technology Networks Premium members only.

Join Technology Networks Premium for free access to:

  • Exclusive articles
  • Presentations from international conferences
  • Over 2,800+ scientific posters on ePosters
  • More than 4,000+ scientific videos on LabTube
  • 35 community eNewsletters

Sign In

Forgotten your details? Click Here
If you are not a member you can join here

*Please note: By logging into you agree to accept the use of cookies. To find out more about the cookies we use and how to delete them, see our privacy policy.

Related Content

Wistar Scientists Decipher Structure of NatA, an Enzyme Complex that Modifies Most Human Proteins
A team of researchers has determined the structure of an enzyme complex that modifies one end of most human proteins and is made at elevated levels in numerous forms of cancer.
Wednesday, August 07, 2013
Scientific News
Non-Disease Proteins Kill Brain Cells
Scientists at the forefront of cutting-edge research into neurodegenerative diseases such as Alzheimer’s and Parkinson’s have shown that the mere presence of protein aggregates may be as important as their form and identity in inducing cell death in brain tissue.
Closing the Loop on an HIV Escape Mechanism
Research team finds that protein motions regulate virus infectivity.
New Class of RNA Tumor Suppressors Identified
Two short, “housekeeping” RNA molecules block cancer growth by binding to an important cancer-associated protein called KRAS. More than a quarter of all human cancers are missing these RNAs.
Gut Microbes Signal to the Brain When They're Full
Don't have room for dessert? The bacteria in your gut may be telling you something.
Turning up the Tap on Microbes Leads to Better Protein Patenting
Mining millions of proteins could become faster and easier with a new technique that may also transform the enzyme-catalyst industry, according to University of California, Davis, researchers.
Exploring the Causes of Cancer
Queen's research to understand the regulation of a cell surface protein involved in cancer.
Measuring microRNAs in Blood to Speed Cancer Detection
A simple, ultrasensitive microRNA sensor holds promise for the design of new diagnostic strategies and, potentially, for the prognosis and treatment of pancreatic and other cancers.
Novel Proteins Linked to Huntington's Disease
University of Florida Health researchers have made a new discovery about Huntington's disease, showing that the gene that causes the fatal disorder makes an unexpected "cocktail" of mutant proteins that accumulate in the brain.
Enzyme Critical to Maintaining Telomere Length Discovered
New method expected to speed understanding of short telomere diseases and cancer.
New Method Identifies Up to Twice as Many Proteins and Peptides
An international team of researchers developed a method that identifies up to twice as many proteins and peptides in mass spectrometry data than conventional approaches.
Scroll Up
Scroll Down
Skyscraper Banner

Skyscraper Banner
Go to LabTube
Go to eposters
Access to the latest scientific news
Exclusive articles
Upload and share your posters on ePosters
Latest presentations and webinars
View a library of 1,800+ scientific and medical posters
2,800+ scientific and medical posters
A library of 2,500+ scientific videos on LabTube
4,000+ scientific videos