Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Cancer risk takes shape

16.10.2001


About half of all patients with hereditary breast or ovarian cancer have mutations in a gene called BRCA1. Now the first images of the protein the gene encodes, BRCA1, are helping researchers work out how the mutations cause human disease.





The pictures reveal fine detail of how BRCA1 interacts with other proteins. Such information should help researchers work out how BRCA1 prevents cells becoming cancerous. They suspect that it is involved in DNA repair, controlling cell division and regulating gene activity.

Understanding BRCA1 should also make it easier to design genetic screening programmes to identify individuals at risk and catch cancer early. This is "very important to long-term survival," says Mark Glover of the University of Alberta in Edmonton, Canada, leader of one of the teams that have solved parts of BRCA1’s structure.


BRCA1 is a big protein — three times the size of haemoglobin, for example. Its chain of 1,863 amino acid links folds into a complex three-dimensional structure. Like a molecular Swiss Army knife, different parts are designed for different jobs.

Most of the mutations associated with breast and ovarian cancers beset the two regions composed of amino acids at the chain ends now under scrutiny. These areas vary least between different species, showing that their function is important enough for natural selection to stamp out slip-ups that would lead to variation.

The ends are probably the most important parts of the molecule, says Richard Baer, a cancer researcher at Columbia University in New York. "They won’t be the whole story, but they’re a big part of the story," he says.

Marked for death

One end of BRCA1 — the ’N’ terminus — bonds to another protein. The two form a catalyst that joins a small molecule called ubiquitin to other proteins. Ubiquitin tags proteins for destruction — an important stage in the body’s defence against cancer.

This much was already known. Rachel Klevit, of the University of Washington in Seattle, and colleagues have now visualized the interface between BRCA1 and its catalytic collaborator using nuclear magnetic resonance spectroscopy.

Klevit’s team was surprised to find that the collaborator joins to a different part of BRCA1 than they had suspected. The structure shows that mutations can disrupt either this junction or the ubiquitin-attachment machinery.

A full understanding of the N-terminal region’s workings might allow mutant BRCA1 proteins to be repaired, using small molecules to enhance or disrupt the protein machine, says Klevit. Unfortunately the many proteins that interact with BRCA1 make this a daunting task.

"We can do these sorts of things on the chalkboard, but until we’re clear on the multiple functions of all these different proteins it’s going to be difficult," says Klevit.

Pack up

Glover’s group focused on the other end of the molecule, the ’C’ terminus. Here, around 100 amino acids form structures known as BRCT repeats. These often feature in proteins that repair DNA — a vital part of tumour suppression.

X-ray crystallography reveals that the two BRCT repeats in BRCA1 "pack in a very intimate manner", says Glover. Mutations that alter the repeats disrupt their packing and unravel the protein. The loss of the last 11 amino acids at the protein’s C terminus is associated with aggressive, early-onset breast cancer.

The structures Klevit’s and Glover’s groups reveal are common to a range of proteins, but between them lies a large stretch of terra incognita, "that doesn’t look like any other protein", says Klevit. These amino acids — more than 1,500 of them — must do something, she says: "Nature’s not wasteful of its resources."


letters
Structure of a BRCA1–BARD1 heterodimeric RING–RING complex

PETER S. BRZOVIC, PONNI RAJAGOPAL, DAVID W. HOYT, MARY-CLAIRE KING & RACHEL E. KLEVIT
Nature Structural Biology 8, 833-837 (October 2001)

letters
Crystal structure of the BRCT repeat region from the breast cancer-associated protein BRCA1

R. SCOTT WILLIAMS, RUTH GREEN & J.N. MARK GLOVER
Nature Structural Biology 8, 838-842 (October 2001)


JOHN WHITFIELD | Nature News Service
Further information:
http://www.nature.com/cancer/hotp/200110/4.html
http://www.nature.com/cancer/

More articles from Health and Medicine:

nachricht 3D images of cancer cells in the body: Medical physicists from Halle present new method
16.05.2018 | Martin-Luther-Universität Halle-Wittenberg

nachricht Better equipped in the fight against lung cancer
16.05.2018 | Friedrich-Alexander-Universität Erlangen-Nürnberg

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: LZH showcases laser material processing of tomorrow at the LASYS 2018

At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.

At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...

Im Focus: Self-illuminating pixels for a new display generation

There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?

At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...

Im Focus: Explanation for puzzling quantum oscillations has been found

So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics

Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...

Im Focus: Dozens of binaries from Milky Way's globular clusters could be detectable by LISA

Next-generation gravitational wave detector in space will complement LIGO on Earth

The historic first detection of gravitational waves from colliding black holes far outside our galaxy opened a new window to understanding the universe. A...

Im Focus: Entangled atoms shine in unison

A team led by Austrian experimental physicist Rainer Blatt has succeeded in characterizing the quantum entanglement of two spatially separated atoms by observing their light emission. This fundamental demonstration could lead to the development of highly sensitive optical gradiometers for the precise measurement of the gravitational field or the earth's magnetic field.

The age of quantum technology has long been heralded. Decades of research into the quantum world have led to the development of methods that make it possible...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Save the date: Forum European Neuroscience – 07-11 July 2018 in Berlin, Germany

02.05.2018 | Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

 
Latest News

Designer cells: artificial enzyme can activate a gene switch

22.05.2018 | Life Sciences

PR of MCC: Carbon removal from atmosphere unavoidable for 1.5 degree target

22.05.2018 | Earth Sciences

Achema 2018: New camera system monitors distillation and helps save energy

22.05.2018 | Trade Fair News

VideoLinks
Science & Research
Overview of more VideoLinks >>>