An international team of scientists
has made a major step forward in our understanding of how enzymes 'edit' genes,
paving the way for correcting genetic diseases in patients.
Researchers at the Universities of
Bristol, MĂĽnster and the Lithuanian Institute of Biotechnology have observed
the process by which a class of enzymes called CRISPR – pronounced 'crisper' –
bind and alter the structure of DNA.
The results, published in the
Proceedings of the National Academy of Sciences (PNAS) today, provide a vital
piece of the puzzle if these genome editing tools are ultimately going to be
used to correct genetic diseases in humans.
CRISPR enzymes were first discovered
in bacteria in the 1980s as an immune defence used by bacteria against invading
viruses. Scientists have more recently shown that one type of CRISPR enzyme –
Cas9 – can be used to edit the human genome - the complete set of genetic information for humans.
These enzymes have been tailored to
accurately target a single combination of letters within the three billion base
pairs of the DNA molecule. This is the equivalent of correcting a single
misspelt word in a 23-volume encyclopaedia.
To find this needle in a haystack,
CRISPR enzymes use a molecule of RNA - a nucleic acid similar in structure to
DNA. The targeting process requires the CRISPR enzymes to pull apart the DNA
strands and insert the RNA to form a sequence-specific structure called an
'R-loop'.
The global team tested the R-loop
model using specially modified microscopes in which single DNA molecules are
stretched in a magnetic field. By altering the twisting force on the DNA, the
researchers could directly monitor R-loop formation events by individual CRISPR
enzymes.
This allowed them to reveal
previously hidden steps in the process and to probe the influence of the
sequence of DNA bases.
Professor Mark Szczelkun, from
Bristol University's School of Biochemistry, said: "An important challenge
in exploiting these exciting genome editing tools is ensuring that only one
specific location in a genome is targeted.
"Our single molecule assays have
led to a greater understanding of the influence of DNA sequence on R-loop
formation. In the future this will help in the rational re-engineering of
CRISPR enzymes to increase their accuracy and minimise off-target effects. This
will be vital if we are to ultimately apply these tools to correct genetic diseases
in patients."
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