Cancer biologists now know quite a bit about how multitalented p53 achieves this, but one aspect of its activities still remains shrouded in mystery. This is its role in maintaining the structural integrity and stability of the mammalian genome – the chromosomes and all the genes they carry.

Albert J. Fornace from the US National Cancer Institute, Bethesda, Maryland and colleagues have now pulled the curtain aside a little by uncovering one of p53's protein partners in this essential activity, which takes the whole process a step nearer to the chromosomes themselves.

In the October issue of Nature Genetics1, Fornace and colleagues report that mice lacking a protein called Gadd45a, whose activity is regulated by p53, show the same sorts of genome defects that occur when p53 itself is absent.

Among the many unwelcome consequences of a lack of either p53 or Gadd is an increased occurrence of chromosomal abnormalities, such as fusion of two different chromosomes, leading to chromosomal breakage when the cell tries to divide. Large numbers of cells from Gadd-deficient mice had also lost individual chromosomes, and others had abnormal duplication of the whole genome so that they contained four copies of each chromosome instead of two. Gadd-deficient mice were also more susceptible than normal mice to radiation-induced cancers.

Gadd appears to act at the stage in cell division when the cell has copied its DNA and is preparing to enter mitosis, the phase of cell division during which the nucleus divides and the duplicated chromosomes are distributed equally to two new cell nuclei. Gadd is known to be able to interact with components of the chromosomes that are involved in ensuring that this distribution occurs correctly. So it is likely that Gadd either detects certain types of chromosomal damage or even prevents it from occurring. If chromosomal damage does occur, the Gadd/p53 pair could then stop the cell in its tracks, causing it to die neatly and quietly, taking its damaged chromosomes to the grave with it.

In the absence of Gadd, cell division would continue, with an increased likelihood at each round of division that the initial DNA damage would give rise to damaged chromosomes, abnormal chromosome numbers and, eventually, to a greatly increased likelihood of the cell becoming cancerous.

The death of an individual cell is rarely a problem for the mammalian body with its billions of cells. The continued survival, division and uncontrolled growth of just a single genetically damaged cell, on the other hand, can be lethal.