A study led by Francis Crick Institute researchers describes the
long sought after biochemical function of an important family of
tumour suppressor proteins.
Called 'Rad51 paralogs', when they're mutated in humans, these
proteins cause breast and ovarian cancer and Fanconi anemia - a
genetic disease that causes leukaemia and bone marrow failure in
most sufferers, alongside other problems.
Dr Martin Taylor of the Crick (currently based at Clare Hall in
Hertfordshire) explained: "The biochemical function of these
proteins has eluded scientists for two decades, because they are
very difficult to work with in many organisms. However we chose to
use a nematode worm as a model organism and discovered that the
proteins were much easier to study."
Using a range of cutting edge biochemical and biophysical
techniques allowed the scientists to discover that Rad51 paralogs
have an important function in stimulating a DNA repair reaction
called homologous recombination, by an unexpected molecular
mechanism. DNA repair is a critical process in cells - when it
fails, unrepaired mutations in the DNA can cause cells to lose
normal controls on their growth and behaviour. This can result in
tumours forming.
Dr Simon Boulton of the Crick (also at Clare Hall) said:
"Homologous recombination is an essential mechanism for the repair
of DNA double strand breaks. It is tightly regulated at each step
of the reaction by mediator proteins, including the well known
tumour suppressor proteins BRCA1 and BRCA2, as well as the Rad51
paralogs.
"The importance of homologousrecombination in human disease is
highlighted by the fact that mutations in any of these proteins can
cause a severe form of Fanconi anaemia, as well as hereditary
breast and ovarian cancers."
He added: "The Rad51 paralogs are just as important as BRCA1 and
BRCA2 but are much less well known because, until now, we didn't
understand how they worked."
At the heart of DNA repair by homologous recombination is a
protein called Rad51, which can form filamentous structures wrapped
around DNA. These structures initiate the DNA repair process. The
Rad51 paralogs are cousins of Rad51.
The scientists found that Rad51 paralogs bind these Rad51-DNA
filaments and alter their structure, making it more flexible,
stable and open. This molecular switch makes Rad51 much more
efficient at DNA repair by homologous recombination. This mechanism
was completely unanticipated and adds a new level of complexity to
our understanding of how homologous recombination is
controlled.
It's hoped that understanding how this important group of tumour
suppressor proteins works will help scientists understand the cause
of the diseases that result when the proteins are mutated.
The paper, Rad51
paralogs remodel pre-synaptic Rad51 filaments to stimulate
homologous recombination, is published in Cell.