Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Structure of DNA repair complex reveals workings of powerful cell motor

The discovery at Scripps Research could usher in a new way of designing non-toxic drugs, researchers say

Over the last years, two teams of researchers at The Scripps Research Institute have steadily built a model of how a powerful DNA repair complex works. Now, their latest discovery provides revolutionary insights into the way the molecular motor inside the complex functions – findings they say may have implications for treatment of disorders ranging from cancer to cystic fibrosis.

In a paper published in an Advance Online Edition of Nature Structural and Molecular Biology March 27, 2011, the scientists say that the complex's motor molecule, known as Rad50, is a surprisingly flexible protein that can change shape and even rotate depending on the task at hand.

The finding solves the long-standing mystery of how a single protein complex known as MRN (Mre11-Rad50-Nbs1) can repair DNA in a number of different, and tricky, ways that seem impossible for "standard issue" proteins to do, say team leaders Scripps Research Professor John Tainer, Ph.D., and Scripps Research Professor Paul Russell, Ph.D., who also collaborated with members of the Lawrence Berkeley National Laboratory on the study.

They say the finding also provides a critical insight into the ABC-ATPase superfamily of molecular motors, of which Rad50 is a member.

"Rad50 and its brethren proteins in this superfamily are biology's general motors," said Tainer, "and if we know how they work, we might be able to control biological outcomes when we need to."

For example, knowing that Rad50 changes its contour to perform a function suggests it might be possible to therapeutically target unique elements in that specific conformation. "There could be a new generation of drugs that are designed not against an active site, like most drugs now (an approach that can cause side effects, but against the shape the protein needs to be in to work," Tainer said.

Russell added, "Proteins are often viewed as static, but we are showing the moving parts in this complex. They are dynamic. They move about and change shape when engaging with other molecules."

First Responder

The MRN complex is known as a first-responder molecule that rushes in to repair serious double-strand breaks in the DNA helix—an event that normally occurs about 10 times a day per cell due to ultraviolet light and radiation damage, etc. If these breaks are not fixed, dangerous chromosomal rearrangements can occur that lead to cancer. Paradoxically, the complex also mends DNA breaks promoted by chemotherapy, protecting cells against cancer treatment.

When MRN senses a break, it activates an alarm telling the cell to shut down division until repairs are made. Then, it binds to ATP (an energy source) and repairs DNA in three different ways, depending on whether two ends of strands need to be joined together or if DNA sequences need to be replicated. "The same complex has to decide the extent of damage and be able to do multiple things," Tainer said. "The mystery was how it can do it all."

To find out, Tainer, head of a structural biology group, and Russell, who leads a yeast genetics laboratory, began collaborating five years ago. With the additional help of team members at Lawrence Berkeley National Laboratory and its Advanced Light Source beamline, called SIBYLS, the collaboration has produced a series of high-resolution images of the crystal structure of parts of all three proteins (rad50, Mre11, and Nbs1), taken from fission yeast and archaea. The scientists also used the lab's X-ray scattering tool to determine the proteins' overall architecture in solution, which approximates how a protein appears in a natural state.

The scientists say that the parts of the complex, when imagined together as a whole unit, resemble an octopus: the head consists of the repair machinery (the Rad50 motor and the Mre11 protein, which is an enzyme that can break bonds between nucleic acids) and the octopus arms are made up of Nbs1 which can grab the molecules needed to help the machinery mend the strands.

In this study, Tainer and Russell were able to produce crystal and X-ray scattering images of parts of where Rad50 and Mre11 touched each other, and what happened when ATP bound to this complex and what it looked like when it didn't.

In these four new structures, they showed that ATP binding allows Rad50 to drastically change its shape. When not bound to ATP, Rad50 is flexible and floppy, but bound to ATP, Rad50 snaps into a ring that presumably closes around DNA in order to repair it.

"We saw a lot of big movement on a molecular scale," said Tainer. "Rad50 is like a rope that can pull. It appears to be a dynamic system of communicating with other molecules, and so we can now see how flexibly linked proteins can alter their physical states to control outcomes in biology."

"We thought ATP allowed Rad50 to change shape, but now we have proof of it and how it works," Russell said. "This is a key part of the MRN puzzle."

An Engine for Many Vehicles

Rad50 and ATP provide the motor and gas for a number of biological machines that operate across species. These machines are linked to a number of disorders, such as cystic fibrosis, which is caused by a defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which is a member of the ABC ATPase superfamily.

"Our study suggests that ABC ATPase proteins are used so often in biology because they can flexibly hook up to so many different things and produce a specific biological outcome," Tainer said.

Given this new prototypic understanding of these motors, Tainer and Russell envision a future in which therapies might be designed that target Rad50 when it changes into a shape that promotes a disease. For example, chemotherapy could be coupled with an agent that prevents the MRN complex from repairing DNA damage, promoting death of cancer cells.

"There are some potentially very cool applications to these findings that we are only beginning to think about," Russell said.

Co-authors of the paper, "ABC ATPase signature helices in Rad50 link nucleotide state to Mre11 interface for DNA repair," include Gareth J. Williams, Soumita SilDas, and Michal Hammel of the Lawrence Berkeley National Laboratory; and R. Scott Williams, Jessica S. Williams, Gabriel Moncalian, Andy Arval, Oliver Limbo, and Grant Guenther of The Scripps Research Institute.

The study was funded by the National Cancer Institute, the National Institutes of Health, and the Department of Energy.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, Scripps Research currently employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Headquartered in La Jolla, California, the institute also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Scripps Florida is located in Jupiter, Florida.

Mika Ono | EurekAlert!
Further information:

More articles from Life Sciences:

nachricht Novel mechanisms of action discovered for the skin cancer medication Imiquimod
21.10.2016 | Technische Universität München

nachricht Second research flight into zero gravity
21.10.2016 | Universität Zürich

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Resolving the mystery of preeclampsia

21.10.2016 | Health and Medicine

Stanford researchers create new special-purpose computer that may someday save us billions

21.10.2016 | Information Technology

From ancient fossils to future cars

21.10.2016 | Materials Sciences

More VideoLinks >>>