Scientists at the Francis Crick Institute have
described the molecular structure of a key tumour suppressor
protein and provided insights into its role in cells.
BRCA1 is a human gene which produces the tumour
suppressor protein of the same name. Mutations in BRCA1 can result
in a 65-75% lifetime probability of developing breast cancer, and
members of families at high risk of breast cancer can be screened
for mutations in the BRCA1 and related BRCA2 genes.
The BRCA1 protein has a key protective role in DNA
repair and so helps to maintain genetic stability.
Mutations in the BRCA1 gene which result in
insufficient or defective production of the BRCA1 protein will
inhibit DNA repair and lead to genetic instability. This genetic
instability increases the likelihood of cancer-causing
mutations.
The BRCA1 protein functions in interaction with
three protein complexes (BRCA1-A, BRCA1-B and BRCA1-C).
Scientists at the Francis Crick Institute have
described the molecular structure of BRCA1-A and provided insights
into its role in deubiquitination, an essential process involved in
modulating DNA repair.
The scientists used a range of cutting-edge
techniques, including electron microscopy, mass spectrometry and
biochemical analysis. Electron microscopy was used to define the
overall shape of the protein complex, but this was not sufficient
to pin-point the exact locations of the individual molecular
components.
A combination of native mass spectrometry and
biochemical analysis was then used to provide the extra information
required to triangulate the location of the components.
In the longer term, it is hoped that a more
detailed understanding of the structure and function of the complex
might inform efforts to develop inhibitors of the BRCA1-A and
linked complexes which might be clinically useful.
Steve Smerdon, Group Leader at the Francis Crick
and final author on the paper, said: "The structure, albeit at low
resolution, is really the first structural glimpse of any of the
major BRCA1 complexes. In a way, the size and complexity is
somewhat surprising since the reaction it catalyses is relatively
simple: the cleavage of a single bond between two linked
ubiquitins. The structure now suggests how the overall architecture
might act to stabilise interactions with ubiquitin chains. More
importantly it also indicates how interaction with BRCA1 itself
might regulate its activity."
The paper, Three-dimensional architecture of the
human BRCA1-A histone deubiquitinase core complex, is published inCell Reports.