DNA replication mystery solved

01 August 2013

Xenopus laevis, or the African clawed toad

Image: Xenopus laevis, or the African clawed toad

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.

  • Scientists at the MRC's National Institute for Medical Research and the Gurdon Institute in Cambridge have discovered four proteins involved in regulating a crucial stage of DNA replication in frog embryos.
  • Embryos and eggs from Xenopus laevis, or the African clawed toad, are widely used as a model organism in biological studies, because Xenopus is relatively straightforward to do experiments in with high precision