Francis Crick Institute scientists have described the mechanism
by which DNA enters and exits the protein rings that enable it to
be packaged into the tiny nucleus inside each of our cells.
Frank Uhlmann of the Crick (currently based at Lincoln's
Inn Fields) explained: "Our genome consists of four metres of
DNA packed into a cell nucleus that is measured in micrometers.
This packaging task is equivalent to stowing the 401 kms of the
London Underground network in a suitcase.
"The means by which this becomes possible are the little
ring-shaped protein machines in the nucleus, the 'SMC complexes'.
They encircle the DNA strand at specific locations to establish the
connections within and between DNA strands that organise the
genome."
The scientists carried out their work in yeast. They began by
purifying one of three SMC complexes found in yeast cells - known
as the 6-subunit cohesin complex - together with a related protein
called the 'cohesin loading complex'. It was the first time that
this has been successfully done. The team then combined these
purified proteins with DNA to biochemically reconstitute the
loading and unloading of the cohesin rings onto DNA. This allowed
them to define the path by which the DNA enters and exits the
protein ring.
Dr Uhlmann said: "Chromosomes arguably are one of the most
important biological structures and they have become an iconic
symbol of the life sciences. To explain the molecular make-up and
functioning of a chromosome is an important conceptual advance in
its own right.
"In addition, it has huge biomedical implications, as SMC
complex mutations are among the most frequent mutations found in
cancer. Furthermore, inherited mutations in regulators of the SMC
complexes are the cause for severe developmental disorders,
including Cornelia de Lange Syndrome and Roberts Syndrome."
The paper, DNA
Entry Into and Exit Out of the Cohesin Ring by an Interlocking Gate
Mechanism, is published in Cell.