Scientists have solved a 30-year puzzle surrounding the
regulation of DNA replication in frog
embryos.
DNA replication occurs as part of cell division, when cells and
their DNA replicate and divide. The process is essential to life
but, if it goes wrong, can cause cancer.
Now, Clara Collart and Jim Smith of the MRC's National Institute
for Medical Research (now part of the Francis Crick
Institute) and Philip Zegerman at the Gurdon Institute
in Cambridge have discovered four factors that control the speed of
DNA replication during embryo development in the frog Xenopus
laevis - something that has perplexed scientists for three
decades.
The embryos of many species, such as fish, flies and frogs,
develop externally in an egg (unlike mammal embryos, which grow and
develop inside their mother's uterus). In these externally
developing embryos, early cell divisions are controlled by genetic
information (in the form of small molecules called messenger RNAs)
and proteins from the mother that are present in the egg. These are
known as maternally inherited factors.
However, after a certain number of cell cycles, new messenger
RNAs are made and replace those inherited from the mother, which
break down.
Dr Collart explained: "Xenopus embryos go through a crucial
developmental event, called the mid-blastula transition, during
which the speed of DNA replication slows down, the cell cycle
lengthens and the embryo starts expressing its own
genes."
As this happens, the number of nuclei - the 'control centres' of
cells, which contain their genetic material - increase
exponentially in the embryo as its cells replicate and divide.
Thirty years ago it was proposed that the lengthening of the cell
cycle is caused by the progressive depletion of one of these
maternally inherited factors as the number of nuclei increase, but
until now exactly what this was and how it worked has remained a
mystery.
In this study, the researchers identified four proteins that
diminish as the number of nuclei in the embryo increase - called
Cut5, RecQ4, Drf1 and Treslin. Known as DNA replication factors,
the team discovered that these proteins slow the speed of DNA
replication at the mid-blastula transition and lengthen the cell
cycle.
Professor Smith said: "These experiments provide the mechanistic
basis for the hypothesis put forward 30 years ago that cell cycle
events at the MBT in Xenopus are regulated by the depletion of
maternally inherited factors."
Dr Collart added: "Every cell has to make a perfect duplicate of
its genome to avoid it becoming unstable and causing cancer. The
process of DNA replication is therefore strictly regulated and it
is crucial to understand how this regulation is achieved. This work
provides an explanation for how the speed of DNA replication is
regulated during development."
The paper, Titration of Four Replication Factors Is Essential for the Xenopus
laevis Midblastula Transition, is published
in Science.