Professor Julian Blow

The Blow lab are studying the signals that our cells use to control replication of their DNA, and how failures in this process can lead to diseases such as cancer.

When a cell divides, its genetic material residing in the chromosomes is copied. Although this may sound simple, it is very complicated and tightly controlled. All the chromosomes need to be copied in their entirety with the minimum of errors. One key control mechanism is called “licensing”. Licensing acts as a marker for where the copying must start. Without it, the genetic material is not copied. When the copying starts, the marker (license) is removed. This stops the genetic material from being copied more than once.

Sometimes mistakes are made in the copying process, which can cause irreversible genetic changes. Some of the changes may have no effect, but others may lead to cells becoming cancerous. The “licensing” control mechanism is often faulty in many early-stage cancer cells. This suggests that it is an important control system for cancer cells to evade.

The lab are interested in how the genetic copying process occurs and is controlled. They hope that their work provides a better understanding of how DNA replication works and could help lead to exciting innovative ideas for future anti-cancer treatments.

The lab uses a range of experimental approaches, but focuses mainly on extracts of frog eggs which faithfully recreate in a test tube the major activities that occur when a cell divides, including the duplication of chromosomes. The use of frog egg extracts provides unparalleled opportunities to study these processes using cutting-edge biochemical techniques. The lab also has expertise in using computer modeling to simulate cell division activities which can then be compared with biochemical results.

Figure: Cartoon of major events in the cell division cycle. The DNA in a single chromosome (curved black line) is shown passing through the four cell cycle stages of G1, S phase (S), G2 and mitosis (M). During late mitosis and G1, the licensing system is active and MCM2-7 hexamers (blue) are loaded onto DNA at sites where replication (copying) will start. At other cell cycle phases, the licensing system is inactive (for example by the expression of the licensing inhibitor geminin); this is crucial to ensure that replicated DNA does not become re-licensed and hence re-replicated. Driven by the increase in CDK activity during S phase, MCM2-7 hexamers are transformed into CMG helicases that drive the copying process (pink). By G2 phase, all the DNA has been replicated and all MCM2-7 hexamers have been displaced from the DNA. During mitosis, the DNA condenses into paired chromatids that are segregated to the two daughter cells.

Selected publications

• The role of DDK and Treslin-MTBP in coordinating replication licensing and pre-Initiation Complex formation Volpi et al. (2021)
• The high-affinity interaction between ORC and DNA that is required for replication licensing is inhibited by 2-Arylquinolin-4-amines. Gardner et al. (2017)
• Reversal of DDK-mediated MCM phosphorylation by Rif1-PP1 restrains initiation of DNA replication in vertebrates. Alver et al. (2017)
• Unreplicated DNA remaining from unperturbed S phases passes through mitosis for resolution in daughter cells. Moreno et al. (2016)
• Buffered Qualitative Stability explains the robustness and evolvability of transcriptional networks. Albergante et al. (2014)
• Xenopus Cdc7 executes its essential function early in S phase and is counteracted by checkpoint-regulated Protein Phosphatase 1. Poh et al. (2014)