Scientists have solved the ornery crystal structure of
a protein that, when mutated, is involved in breast cancer.
The study confirms the protein's role in DNA repair and
should help elucidate how DNA repair can break down and
lead to cancer. But it leaves plenty of thorny questions
unanswered.
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DNA repair kit. BRCA2 repairs a stretch
of DNA using a matching strand as a template.
CREDIT: H. YANG ET AL., SCIENCE
297, 1837 (13 SEPTEMBER 2002) |
For many years, scientists have known that mutations
in the genes coding for the proteins BRCA1 and BRCA2
increase risk of breast and ovarian cancer by 30% to
70% and account for half of all hereditary cases of
the diseases. They have also had several clues that
the proteins are involved in DNA repair: They consort
with known repair proteins, and mutant versions make
cells virtually unable to repair DNA when both strands
of the double helix are broken. Poor repair of these
"double-strand breaks" can activate cancer-causing genes
or inactivate tumor-suppressor genes. But BRCA2 is a
large, fussy molecule, difficult to isolate and characterize
with x-ray crystallography. So nobody knew its structure
or whether it directly contacts DNA during repair or,
like BRCA1, plays an indirect role.
To profile BRCA2, researchers stabilized it by combining
it with DSS1, another repair protein. This let them
describe the structure of its tail end, which provided
near-ironclad evidence that BRCA2 gets down and dirty
with DNA. It contains three binding sites for single-stranded
DNA and has a so-called tower domain: a bundle of helices
that resembles the structures other organisms use to
bind double-stranded DNA. The researchers also showed
that BRCA2 helps other repair proteins using a template
to turn a single-stranded DNA fragment into a longer
double strand, a process integral to the repair of double-strand
breaks. The team, led by Nikola Pavletich of the Memorial
Sloan-Kettering Cancer Center in New York City, reports
the findings in the 13 September issue of Science.
The study "provides a striking view of the protein
and the way in which it functions as a caretaker of
the genome," says oncologist Bert Vogelstein of Johns
Hopkins University School of Medicine in Baltimore,
Maryland. It also brings up crucial questions for future
research: Scientists still don't know how particular
mutations cause cancer, why they lead to cancer in some
tissues and not others, or what might be done to counteract
the mutations.
--BEN SHOUSE
Related sites
Pavletich's
site
The
abstract, with link to full text
Diagram
of BRCA2's possible function
