p53 orchestrates DNA replication restart homeostasis by suppressing mutagenic RAD52 and POLθ pathways

When a cell divides to make more cells, it duplicates its DNA to pass on an identical set of genes to the new cell. Copying DNA – also known as DNA replication – is a complex process that involves several steps. First, the double helix gradually unwinds and unzips to separate the DNA strands. This creates a molecule known as the ‘replication fork’. Then, copies of each strand are created and proofread for errors. Eventually, the strands are sealed back together so that the helices contain one old and one new part. But sometimes errors sneak in during DNA replication, which can lead to mutations that may cause cancer. The higher the number of mutations, the bigger the chance is that the cancer becomes aggressive and resistant to therapy. Some of the most common mutations found in tumors happen in a protein called p53. This protein is known to stop tumors from growing by selectively killing cells with mutations. When p53 is faulty, mutant cells no longer die and can grow uncontrollably to form tumors. However, its killing abilities do not fully explain how p53 protects cells from accumulating mutations that can cause cancer, and until now, it was not known if p53 also had any other roles. Now, Schlacher et al. discovered that p53 can protect the DNA from mutations. The experiments used normal cells and cancer cells from humans and mice, in which p53 was either blocked or modified. The experiments revealed that p53 plays an important role during DNA replication. When p53 is ‘healthy’, it binds to the replication fork. This ensures that replication restarts properly after it has passed faulty patches of the DNA. The p53 protein also helps to organize the proteins involved in DNA replication. When p53 was absent or mutated, the DNA-repair protein that usually binds to the fork failed to attach properly. Instead, other proteins prone to make mutations took over the replication fork and created a pattern of mutations commonly found in tumors resistant to treatment. A next step will be to investigate p53’s role at damaged DNA replication forks and how it interacts with other proteins involved in DNA replication. To fully understand all roles that p53 plays in preventing tumor growth can help to find new ways to treat tumors with p53 defects or tumors that have become resistant to treatment.