Complementary and collaborative research from the research groups of Professor Julian Blow and Professor Tim Newman has been published in two sister papers in Proceedings of the National Academy of Sciences (PNAS). The work focuses on experimental and theoretical evidence that unreplicated DNA can pass through mitosis for resolution in the following cell cycle.
“Textbooks tell us that in eukaryotes the genome is replicated exactly once per cell cycle, with no sections left unreplicated and no sections replicated more than once. Our papers provide strong theoretical and experimental evidence that this is not true for organisms with Gigabase-sized genomes such as humans,” said Professor Blow. “In almost all cell cycles, one or more stretches of unreplicated DNA from the mother cell will persist (due to a “double fork stall”) when cells enter mitosis, and this unreplicated DNA is segregated to daughter cells for ultimate resolution in the next S phase.”
“The theoretical work was led by Dr Rana Al Mamun, assisted by Dr Luca Albergante, and formed the basis of Rana’s PhD thesis. From the theory we predict that as genome sizes get larger than about 100 Megabases, replication errors become highly likely, although occurring in small numbers, and hence are a significant challenge for cells. Mechanisms to repair the dramatic errors caused by double fork stalls are therefore required to allow eukaryotes to evolve to higher complexity, and Julian's experiments reveal a strong candidate mechanism for this,” explained Professor Newman.
Experimental work led by Alberto Moreno and Jamie Carrington provides evidence that this unreplicated DNA is passed through mitosis via structures called Ultrafine Anaphase Bridges, after which they are recognised by the 53BP1 protein to form ‘53BP1 Nuclear Bodies’. They show that the abundances of 53BP1 Nuclear Bodies and Ultrafine Anaphase Bridges closely match theoretical predictions when the number of origins is experimentally increased or decreased.
The striking convergence of theory and experimental data from these two studies provide insights into the challenges evolution has had to overcome in allowing genomes to grow larger than tens of Megabases, thus allowing higher eukaryotic complexity.
Both papers are currently available online in the journal PNAS.