Zinc-Bound Protein Implicated in DNA Repair

Curing cancer is not just for medical doctors, hospitals, and pharmaceutical companies anymore. Basic biological research at Lawrence Berkeley National Laboratory has helped build the framework to assist in the pursuit of this elusive goal.

Researchers at Berkeley Lab have played a pivotal role in the discovery of a novel "zinc hook," part of a protein complex essential for DNA repair.

This DNA repair machine, known as the Mre11 complex, contains a compact, DNA binding head and an elongated tail.

The tail contains a unique shape known as a "coiled coil" that resembles a slinky pulled into shape of the letter "U". At the bottom of the loop is a unique hook that allows the tail to connect with the tail of another Mre11 complex.

A zinc atom at the hook coordinates the two tails together, forming the distinctive "zinc hook" structure.

This discovery suggests a specific role for the Mre11 complex.

Since the head can bind to a DNA strand and the tails can bind each other, the complex likely plays a role in bringing stretches of DNA together.

Detailed in the August 1 issue of the scientific journal Nature, the research has been one of the first fruits to spring from the Structural Cell Biology of DNA Repair Machines (SBDR) project, a $19 million effort being funded by the National Cancer Institute.

Based at the Berkeley Lab, the SBDR project involves over 12 scientific institutions and 17 investigators.

The SBDR project is geared towards understanding almost every known aspect of DNA repair, said lead project investigator Priscilla Cooper.

DNA, the code of life, is subject to damage by chemicals, radiation, and copying errors.

Repair mechanisms are essential to the health of an organism, with dysfunctional machinery increasing the risk of many forms of cancer.

As scientists better understand the processes of DNA repair, they will be able to perform preventive diagnoses. Drugs can be designed to hinder DNA repair in cancerous cells, bolstering chemotherapy treatments.

DNA repair is made more complicated when both intertwining strands are damanged simultaneously.

In such a case, one repair method is to find a similar stretch of DNA, bring it near the damaged DNA, and make a new copy. A cruder method is to simply join the broken ends together.

The newly characterized protein complex plays a role in both methods, as well as other processes involving the binding of two DNA strands.

Despite being the product of an extensively collaborative effort, the zinc hook discovery would not have been possible without a new approach to protein research.

"The way people have studied (proteins) is as if they were multi-purpose tools and they have several activities, but we're finding that they are self-assembling machines working in an integrated way," said SBDR project principal investigator John Tainer.

Tainer compared the study of a protein complex to the examination of an automobile. One cannot simply study a spark plug or steering wheel, but must also look at the entire vehicle.

In studying the Mre11 complex, Tainer used electron microscopy to look at the bigger picture of the metaphorical car and x-ray crystallography to examine the detailed structure under the hood.

Keeping with the spirit of the SBDR, a team of Berkeley Lab physicists and engineers are designing a new x-ray crystallography beamline to be attached to Berkeley Lab's existing Advanced Light Source. The new beamline will aid in extending the results of the current study.

"The beamline design represents an unique departure from current beamline design in that it is tailored for the study of large macromolecular complexes like those that mediate DNA repair," said Berkeley Lab scientist Susan Tsutakawa, a member of the research team.

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